Abstract
Guanosine triphosphatases intervene in: (1) signal transduction from the intracellular edge of the plasma membrane and intracellular domain of transmembrane receptors; (2) protein synthesis at the ribosome (Vol. 1 – Chap. 5. Protein Synthesis); (3) control of cell division (Vol. 2 – Chap. 2. Cell Growth and Proliferation); (4) proper protein folding; (5) translocation of proteins through the membrane of the endoplasmic reticulum; and (6) vesicular transport within the cell (Vol. 1 – Chap. 9. Intracellular Transport).
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Notes
- 1.
The signal recognition particle (SRP) binds to newly synthesized peptides that emerge from ribosomes, thereby coupling protein translation to protein translocation through the protein-conducting channel, the so-called translocon, in the endoplasmic reticulum membrane. Once SRP is connected to the SRP receptor (SRPR), the nascent peptide chain is inserted into the translocon and, then, enters into the endoplasmic reticulum. The SRP-SRPR complex dissociates via GTP hydrolysis.
- 2.
The GTP hydrolysis rate of dynamins accelerates in the presence of microtubules, liposomes, and certain SH3 domain-containing proteins, to which dynamin can link. Its monomers self-associate into homodimers that connect each other to form homotetramers for optimal GTPase activity [773]. Dynamin is able to build homo-oligomers and polymers. Its membrane binding and self-association occur independently from its nucleotide-bound state. Dynamin operates in the scission of newly formed, coated vesicles from the membrane of native compartment for their release and fusion with recipient compartment. Dynamin also intervenes in cytokinesis and division of organelles. The dynamin family includes classical dynamins, dynamin-like proteins, interferon-induced GTP-binding protein Myxovirus resistance proteins (Mx), and mitochondrial membrane proteins mitofusins. In mammals, 3 known dynamin types are encoded by 3 genes: dynamin-1 in neurons and neuroendocrine cells; dynamin-2 in most cell types; and dynamin-3 strongly produced in testes and, to a lesser extent, in the brain, heart, and lung. Dynamins are founding member of a family of dynamin-like GTPases. Dynamin-like proteins include atlastin, or GTP-binding protein GBP3, dynamin-related protein DRP1, optic atrophy 1 homolog (OpA1), and mitofusin-1 and -2. They localize to sites of membrane fission and fusion in the endoplasmic reticulum, mitochondria, and peroxisomes.
- 3.
Septins constitute a group of GTP-binding, hetero-oligomeric proteins that can form filaments. They are involved in different stages of the cell cycle. Septins also participate in secretion, membrane remodeling, and cytoskeleton dynamics. Post-translational modifications and partners regulate septin filament function. Binding of GTP induces conformational changes. Binding of GTP and hydrolysis influence the stability of septin interfaces and contribute to septin filament assembly and disassembly [774].
- 4.
Heterotrimeric guanine nucleotide-binding proteins, monomeric small guanosine triphosphatases, and related ATP-binding proteins are P-loop proteins. Guanosine triphosphatases can be subdivided into conventional guanosine triphosphatases and G proteins activated by nucleotide-dependent dimerization. Conventional guanosine triphosphatases include small GTPases of the RAS superfamily that form heterodimeric complexes with their cognate GTPase-activating proteins. G proteins activated by dimerization are not regulated by guanine nucleotide-exchange factors and GTPase-activating proteins [775].
- 5.
Chaperonins has been classified into 2 groups: group-1 chaperonins that possess 14 subunits and localize to organelles such as mitochondria (e.g., HSP60) and cytoplasm and group-2 chaperonins that have 16 or 18 subunits and reside in the cytosol.
- 6.
A.k.a. TCP1 ring complex (TRiC).
- 7.
Two motifs of small GTPases — switch-1 and -2 — recognize the nature of the bound nucleotide and change their conformation accordingly. These 2 switch domains signal the nucleotide status of the GTPase to effectors or regulators, as they influence between-protein interactions with these binding partners.
- 8.
Each member of the GPCR superclass has a similar structure with 7 transmembrane helices, extracellular amino (N)- and intracellular carboxy (C)-termini, and 3 interhelical loops on each side of the plasma membrane. G-protein-coupled receptors form both homo- and heterodimers. When a single element of the dimer bind to its ligand, the dimer cannot fully activate the linked G protein. Besides, when 2 receptors dimerize to form a signaling unit, the signal can differ from the response given by either receptor alone. Furthermore, the heterodimerization of a GPCR with another affects the functioning of the bound GPCR, modulating its activity.
- 9.
A.k.a. Akt (PKB) phosphorylation enhancer (APE), Gα-interacting vesicle-associated protein (GIV), Hook-related protein HkRP1, and coiled-coil domain-containing protein CCDC88a.
- 10.
Protein kinase-B phosphorylates girdin at Ser1416 in lamellipodia of migrating cells.
- 11.
Protein kinase-B contributes to tumor growth and metastasis, as it activates nuclear factor-κB, target of rapamycin, double minute-2, BCLxL/BCL2-associated death promoter homolog, and matrix metallopeptidases on the one hand and inactivates tuberous sclerosis complex-2, cyclin-dependent kinase inhibitor CKI1b, and FoxO transcription factor on the other.
- 12.
Girdin acts as a signal amplifier for PKB signaling. A threshold of GEF activity exists in the PKB activation by girdin in different cell types and by various stimuli [783]. Signaling from PKB is minimal at low GEF activity. It abruptly rises to reach a maximum above a threshold of GEF activity (switch-like behavior or all-or-none response). Girdin aims at amplifying signaling to initiate cell migration. The regulated amplification of the input signal is associated with slight changes in girdin’s GEF activity close to a certain threshold that allows a rapid cell decision toward motion.
- 13.
Receptor EGFR is internalized mitogenic signals are then executed.
- 14.
A.k.a. axonal membrane protein B50, neural phosphoprotein PP46, and neuromodulin.
- 15.
The neuropeptide galanin resides in the central and peripheral nervous systems and digestive neuroendocrine system. It is coexpressed with many neurotransmitters. It functions as an inhibitor. It operates in metabolism, feeding, learning and memory, nociception, spinal reflexes, neuron regeneration, and anxiety. In particular, galanin precludes cAMP production and activates G-protein-regulated inwardly rectifying K + channels.
- 16.
Proteins Gi1 to Gi3 as well as Go1 and Go2 are synthesized in pancreatic islets. However, Go2 is the major transducer that mediates inhibition of insulin release. It intervenes in galanin effects on ATP-sensitive KIR6.2 (activation) and CaV1 (inhibition) channels, thereby regulating exocytosis.
- 17.
RhoGEF11 is also identified as PDZRhoGEF; RhoGEF12 as leukemia-associated RhoGEF (LARG); RhoGEF25 as GEFT and p63RhoGEF; RhoGEF13 as AKAP13, AKAP-LBC, and LBC-RhoGEF. The latter functions as an A-kinase-anchoring protein (AKAP) and a Rho-selective guanine nucleotide-exchange factor. Expression of AKAP13 is restricted to human hematopoietic cells as well as lung, heart, and skeletal muscle.
- 18.
Activation of phospholipase-C by Gαq causes IP3 production that triggers activation of calcium-dependent protein kinase-C. On the other hand, AT1 phosphorylation by G-protein-coupled receptor kinase increases AT1 avidity for β-arrestin and uncouples AT1 from G-protein. Both signaling from AT1 based on the MAPK module and AT1-mediated transactivation of receptor Tyr kinases can be initiated by both AT1-primed activation of G-protein and the βArr–AT1 complex.
- 19.
G-protein-coupled receptors can activate ERK1 and ERK2 via both G-protein-dependent and -independent mechanisms and different pools of β-arrestins. For example, stimulation of Gαs-coupled V2 vasopressin receptor in rat renal medulla collecting ducts provokes translocation of aquaporin-2 to apical membranes to foster water reabsorption (Gs–ACase–cAMP pathway). Vasopressin V2 receptor can also activate ERK1 and ERK2 upon stimulation of G proteins as well as upon RTK (EGFR, FGFR, IGFR, NTRK1, PDGFR, and VEGFR) transactivation (independently of Gs, Gi, Gq, or Gβγ subunit). β-Arrestins not only act as GPCR regulators, but also as signal transducers of the MAPK module and as activators of Src kinase. Receptor Tyr kinases can recruit β-arrestins once bound to their respective growth factors. In particular, β-arrestins contribute to the activation of ERK1, ERK2, and PI3K by the IGFR–IGF1 complex [794]. Receptor IGFR can be transactivated by thrombin, μ-opioid, GABA B , and AT1 receptors. After Src-dependent shedding by a membrane-associated metallopeptidase of an activator of the insulin-like growth factor receptor for auto- and paracrine signaling, β-arrestins that promotes the GPCR-mediated ERK1/2 activation are engaged by the transactivated IGFR, but not by V2 [794]. β-Arrestins operate in other transactivation types, as they are also involved in transactivation from platelet-activating factor receptor [794].
- 20.
Kinase GRK6 is more efficient than GRK2 on the recruitment of β-arrestin to AT1 and β-arrestin conformational changes [795]. The effect of GRK6 relies on the agonist type. It remains mild for angiotensin-2.
- 21.
For some agonist types, the magnitude of conformational rearrangement of β-arrestin is well correlated with the extent of recruitment to AT1 receptor. For other ligand types, the magnitude of recruitment and of conformational change are not correlated. The extent of β-arrestin conformational change can be indeed lower for an equivalent degree of recruitment to AT1 receptor [795].
- 22.
A.k.a. p115RhoGEF.
- 23.
A.k.a. PDZRhoGEF.
- 24.
A.k.a. leukemia-associated RhoGEF (LARG).
- 25.
A.k.a. lymphoid blast crisis (LBC)-RhoGEF, AKAP13, and AKAP-LBC.
- 26.
A.k.a. GAP1m, as it is related to GTPase-activating protein GAP1, or inositol (1,3,4,5)-tetrakisphosphate-binding protein IP4BP1 with a different subcellular distribution. Whereas GAP1 is located solely at the plasma membrane, RasA2 (or GAP1m) lodges in the perinuclear region.
- 27.
C-class RGS proteins act as conventional Gβγ dimers, as they couple Gα subunits to GPCRs.
- 28.
Both RhoGEF11 and RhoGEF12 bind plexin-B1, a transmembrane receptor for semaphorin Sema4D.
- 29.
For example, RhoGEF12 and RhoGEF11 couple peptidase-activated receptor PAR1 and lysophosphatidic acid receptor, respectively [811]. Protein RhoGEF12 also couples insulin-like growth factor receptor IGF1R for possible crosstalk between GPCRs and RTKs to converge toward RhoA-mediated cytoskeletal rearrangement.
- 30.
A.k.a. AGS3.
- 31.
A.k.a. AGS3-like and Leu(L)–Gly(G)–Asn(N) repeat-containing protein (LGN).
- 32.
A.k.a. G18.
- 33.
A.k.a. Purkinje cell protein PCP2.
- 34.
At low [Ca\({}^{++}\)] i , GAP activity of RGS4 is hampered by PIP3. Hence, Gq/11 stimulates phospholipase-C that raises [Ca\({}^{++}\)] i . Ca\({}^{++}\) then binds to calmodulin. Ca\({}^{++}\)–calmodulin reduces Gq/11 activation and [Ca\({}^{++}\)] i decays. When Ca\({}^{++}\)–calmodulin complex is dissociated, PIP3 inhibition of RGS4 is restored.
- 35.
Protein kinase-C phosphorylates RGS2, thereby decreasing its Gq/11 inhibition. The cGMP-dependent protein kinase PKG phosphorylates RGS4, inducing its translocation to the plasma membrane. Protein kinase-A phosphorylates RGS9, thus inhibiting the GAP activity on Gt.
- 36.
Receptor Tyr kinases regulate phosphoinositide activity.
- 37.
In rat, the majority of RGS8 binds to Go and Gi3. Protein RGS8 can also interact weakly with Gi1, Gi2, Gz, and Gq/11.
- 38.
Protein RGS8 binds strongly to M1 mAChR, but weakly to M3 mAChR receptor. It also tethers to melanin-concentrating hormone receptor (MCH1R) [814]. It can also form a quarternary complex with liganded GABAB1b and GABAB2 receptors and Gi2 or GoA.
- 39.
A.k.a. spinophilin and neurabin-2 (neural tissue-specific Factin-binding protein).
- 40.
Endothelin-1 has positive inotropic effects and stimulates heart wall growth via Gq activation.
- 41.
Binding of ACh to cardiac muscarinic M2 receptors enables GTP to replace GDP at the Gα-subunit of Gi/o-proteins. The subunits dissociate and Gβγ subunit activates K + channels. Phosphatidylinositol (1,4,5)-trisphosphate inhibits RGS activity on Gαi∕o subunits. The rising intracellular Ca\({}^{++}\) concentration leads to the formation of Ca\({}^{++}\)–calmodulin complexes. Calcium–calmodulin binds to RGS, then inhibits the effect of phosphatidylinositol trisphosphate and activates RGS. Consequently, K + channels are inactivated. With decaying intracellular Ca\({}^{++}\) concentration, Ca\({}^{++}\)–calmodulin dissociates and phosphatidylinositol-trisphosphate inhibits RGS again.
- 42.
A.k.a. RGS and PHOX domain-containing protein RGSPX1.
- 43.
A.k.a. RIC8 and synembryn.
- 44.
Adenylate cyclase-5 can also be inhibited by Gi, Gz, and RGS2, as well as protein kinase-A.
- 45.
A splice variant of AGS3 lacking TPR domains is expressed in the heart.
- 46.
Angiotensin-2 receptor AT1 tethers ATRAP that can then impede signaling (cell proliferation and vascular remodeling) by enhancing AT1 endocytosis.
- 47.
Protein GIPC1 interacts with β1-adrenoceptor, dopamine receptor D3, neurotrophic Tyr receptor kinases NTRK1 and NTRK2, RGS19, α5- and α6-integrins, myosin-1C and -6, α-actinin-1, GluT1, low-density lipoprotein receptor-related proteins LRP1, LRP2, and LRP8, as well as KIF1b kinesin [251].
- 48.
Spinophilin is a regulatory subunit of protein phosphatase-1.
- 49.
Sodium–hydrogen exchanger-regulating factor NHERF1 interacts with β2-adrenoceptor, once the latter is phosphorylated by GRK5 kinase. Protein NHERF1 also mediates recycling of internalized β2-adrenoceptors.
- 50.
A.k.a. activator of G-protein signaling AGS1. Protein RasD1 interacts with nitric oxide synthase NOS1 and its adaptor NOS1AP (or CaPON), as well as Gαi [251].
- 51.
A.k.a. Ras homolog enriched in striatum (RHES). The RasD2 protein links to cRaf and PI3K [251].
- 52.
A.k.a. Ris.
- 53.
A.k.a. Rab44.
- 54.
A.k.a. cell migration-inducing protein MIg5, teratocarcinoma protein TC25, and p21Rac1.
- 55.
A.k.a. RacB.
- 56.
A.k.a. Rap1-interacting factor-1 (RIF1).
- 57.
A.k.a. TC10-like protein (TCL).
- 58.
A.k.a. TC10.
- 59.
A.k.a. Wnt1-responsive CDC42 homolog WRCH1.
- 60.
A.k.a. WRCH2 and Chp.
- 61.
A.k.a. RhoE.
- 62.
GPCR ligands, such as thrombin, endothelin, prostaglandin-E2, angiotensin, α-adrenergics, sphingolipids, etc., activate Rho GTPases.
- 63.
Ezrin, radixin, and moesin are involved in membrane recruitment of Rho GTPases. In endothelial cells, RhoA colocalizes with ERM proteins [835].
- 64.
The name of these monomeric GTPases comes from their ability to act as cofactors for cholera toxin-catalyzed adpribosylation of heterotrimeric G-protein subunit Gαs. Six ARF proteins (ARF1–ARF6) operate as cofactors that stimulate the adpribosylating activity of cholera toxin. Yet, the function of ARFs does not involve adpribosylation.
- 65.
Subtypes ARF1 to ARF5 localize to the Golgi body, whereas ARF6 resides at the cell surface.
- 66.
Alias ARP1 used to designate ARF-related protein should be avoided, as ARP means actin-related protein.
- 67.
Small ARL GTPases are related to ARFs structurally, but not functionally or phylogenetically.
- 68.
A.k.a. RING finger protein-46 (RNF46).
- 69.
This protein should not be confused with N-terminal acetyltransferase complex ArD1 (cell division-arrest defective) catalytic subunit homologs (ArD1a and ArD1b, also called Nα-acetyltransferase-10 and -11).
- 70.
ARF1 regulates the early secretory pathway, from the Golgi body to the endoplasmic reticulum and between Golgi cisternae, recruiting coat protein complex-1, clathrin, and adaptor proteins (AP1, AP3, and AP4) [840]. ARF1 also interacts with membrin and SNAREs. ARF6 is located at the plasma membrane and endosomal compartments, where it regulates endocytic membrane trafficking and actin remodeling. It recruits clathrin and AP2. ARF6 acts on phosphatidylinositol 4-phosphate 5-kinase and phospholipase-D, for production of phosphatidylinositol (4,5)-bisphosphate.
- 71.
The myristoylated N-terminal helix is inserted into membrane upon GTP binding. Unlike other small GTPases of the RAS superfamily, which have a long C-terminal linker with a lipid membrane anchor, thereby being located at some distance from the membrane, ARFs are very close to the membrane surface.
- 72.
In humans, 15 ArfGEFs have been identified. They are classified into 6 categories.
- 73.
In mammals, 31 ArfGAPs have been detected. They are categorized into 9 sets.
- 74.
Dual Rab11–ARF-interacting proteins arfophilin-1 and -2 are also called members of family of Rab11-interacting proteins FIP3 and FIP4. They function in the delivery of recycling endosomes to the cleavage furrow. They selectively bind ARF6 GTPAse.
- 75.
Munc18 (mammalian homolog of uncoordinated mutant Unc18) that is also called syntaxin-binding protein StxBP1 is a regulator of Ca\({}^{++}\)-regulated exocytosis in neurons and neuroendocrine cells as well as platelets, adipocytes, etc. Mammalian MInt proteins are homologs of Lin10 in Caenorhabditis elegans. In conjunction with Ca\({}^{++}\)–calmodulin-dependent Ser/Thr protein kinase-3, or membrane-associated guanylate kinase-2 (CaSK, CaMGuK2, or Lin2 homolog) of the MAGUK family, and Lin7 (a.k.a. vertebrate Lin7 homolog [VeLi] and mammalian Lin-Seven homolog MaLS1), MInt proteins that form MInt–CaSK–Lin7 complexes are required for a precise targeting and localization of certain membrane proteins. The MInt proteins bind to the Munc18–syntaxin complex involved in synaptic vesicle fusion. In the central nervous system, MInt substances are scaffolding and trafficking proteins that associate via Disc large homolog DLg1 (or synapse-associated protein SAP97) with inward rectifier potassium channels KIR2.1 to KIR2.3, which control cell excitability [843].
- 76.
CoP1-coated vesicles that bud off the Golgi body contain 2 major transmembrane proteins, i.e., Golgi cargo receptors, that travel between the intermediate compartment and the Golgi body: transmembrane EMP24 domain-containing proteins (TMED). In Saccharomyces cerevisiae, 2 molecules encoded by the Emp24 (EMP24: endomembrane protein of 24 kDa) and Erv25 (ERV25: endoplasmic reticulum vesicle protein of 25 kDa) genes, members of the budding yeast P24 family (EMP24, ERV25, and ERP1–ERP6), heterodimerize for an efficient transport of target proteins from the endoplasmic reticulum to the Golgi body. They localize to both CoP1 + and CoP2 + vesicles as well as endoplasmic reticulum and Golgi membranes. Proteins Emp24 and Erv25 complex. Furthermore, Emp24 and Erv25 depend on each other for stability and incorporation into CoP2-coated vesicles. Type-1 transmembrane protein Emp24 is identical to 24-kDa protein (P24). Transmembrane trafficking proteins TMED2 and TMED3 correspond to membrane proteins P24α and P24β, respectively. Protein P24α is also called transmembrane Emp24-domain-containing trafficking protein TMEδ2. Proteins TMED3 and TMED10 complex. Protein TMED10 is also named P23, P24δ, and transmembrane protein TMP21. In humans, 2 TMP21 variants exist — TMP21-1 and TMP21-2; TMP21-2 is transcribed, but not translated [846]. Protein TMED10 thus corresponds to TMP21-1.
- 77.
Newly synthesized membrane proteins and lipids are conveyed from the endoplasmic reticulum to the Golgi body.
- 78.
In mammals, PI4K3α isoform is predominantly expressed in the brain, whereas PI4K3β is more spread.
- 79.
All isoforms PI(4)P5K1α, PI(4)P5K1β, and PI(4)P5K1γ synthesize PI(4,5)P2.
- 80.
Protein ARF1 facilitates the recruitment of CDC42GTP via the γ-subunit of the coatomer. The CDC42 effector nWASP activates the ARP2–ARP3 actin-nucleating complex.
- 81.
A.k.a. membrane attack complex inhibition factor (MACIP), and protectin.
- 82.
Arfophilin-1 and -2 form complexes with Rab11 and ARF6 GTPases.
- 83.
I.e., ARNO, or PSCD2, ARNO2, or PSCD1, ARNO3, or PSCD3, and ARNO4, or PSCD4.
- 84.
Previously named ARF4L, ARL4L, ARL5, ARL6, and ARL9 [850].
- 85.
One should avoid alias ARP1 because ARP is used for actin-related protein.
- 86.
Ubiquitination by ARD1 of NFκB essential modulator (NEMo), or IKKγ regulatory subunit, is used during antiviral innate and inflammatory responses launched by Toll-like receptor TLR3.
- 87.
A.k.a. ataxia telangiectasia group D-associated protein (ATDC).
- 88.
The stability and activity of P53 transcription factor is regulated by several ubiquitin ligases, not only DM2, but also caspase recruitment domain-containing protein CaRD16, ring finger and CHY zinc finger domain-containing protein RCHY1, as well as Tripartite motif (TriM) proteins TriM24, whereas TriM29 inhibits P53 via its repression of KAT5 acetyltransferase.
- 89.
Filopodia are thin protrusions that contain parallel bundles of actin filaments that extend from the leading edge of migratory cells.
- 90.
As microtubules are organized by the centrosome, microtubule-dependent transfer toward the cell cortex requires plus-end-directed nanomotors of the kinesin superfamily.
- 91.
Intrinsic GTP hydrolysis by Rab GTPases is slow, but is significantly heightened by RabGAPs that accelerate Rab conversion to inactive, GDP-bound form.
- 92.
Small Rab1 and Rab2 GTPases mediate endoplasmic reticulum–Golgi body and Golgi body–endoplasmic reticulum transfer, respectively.
- 93.
Protein Rab5 mediates endocytosis and endosome fusion of clathrin-coated vesicles, macropinocytosis with Rab34, and maturation of early phagosomes with Rab14 and Rab22 GTPases.
- 94.
Three known isoforms of Rab6 exist (Rab6a–Rab6c) [857]. Isoforms Rab6a and Rab6b are encoded by separate genes, whereas Rab6a and Rab6c are splice variants. Isoforms Rab6a and Rab6c are ubiquitous, whereas Rab6b is mainly expressed in the brain. Molecule Rab6a localizes to the Golgi body. Protein Rab6a inhibits anterograde and hastens retrograde intra-Golgi transport. In addition to Rab6, Rab33 and Rab40 mediate intra-Golgi transfer.
- 95.
A dendogram is a tree for visual classification based on structural and/or functional similarity of molecular species.
- 96.
Protein RabGDI forms a cytosolic heterodimer with Rab GTPase for sequestration. This complex is targeted for recruitment of Rabs to cognate membrane.
- 97.
On endosomes, Rab5 recruits GEF for Rab7 that allows maturation of early endosomes into late endosomes [861]. Activation of Rab7 then associates with inactivation of Rab5 agent. Therefore, predominant resident Rab isoform determines the compartment identity.
- 98.
Iporin also binds to golgin-A2.
- 99.
microtubule-associated monoxygenase, calponin, and LIM domain-containing proteins (MiCaL1–MiCaL3) are predominantly cytosolic Rab1-interacting proteins that bind cytoskeletal components, such as intermediate filament vimentin, and actin.
- 100.
Member Rab11FIP3 involved in localization of recycling endosomes binds to Rab11a and Rab11b, Rab25, ARF6, RhoAGAP Cyk4, and ARF1GAP ASAP1 [866].
- 101.
These effectors, in fact, target members of both group-3 and -8 Rab GTPases.
- 102.
Synaptotagmin-like protein SytL4 is also called granuphilin-a.
- 103.
The C2 domain is a motif of various mediators involved in vesicular trafficking. It serves as a binding site both Ca\({}^{++}\) and membrane phospholipids. Among various C2 domain-containing proteins, 4 families of C-terminal tandem C2 domain-containing proteins (C2a and C2b) exist: double C2-like proteins (DoC2), rabphilin, synaptotagmin (Syt), and Syt-like protein (SLP). The C2a domain regulates fusion of synaptic vesicles for neurotransmitter release. The C2b domain is a binding motif for phosphatidylinositol trisphosphate and bisphosphate in the absence and presence of calcium ions, respectively. Subtype DoC2a that is mainly expressed in the central nervous system and ubiquitous DoC2b are involved in Ca\({}^{++}\)-dependent neurotransmitter release and intracellular vesicle trafficking, respectively. Rabphilin-3 also regulates neurotransmitter release in hippocampal neurons. Synaptotagmins are calcium sensors that intervene in the regulation of neurotransmitter release and hormone secretion. Only 8 synaptotagmins among 15 synaptotagmins bind to calcium (synaptotagmins-1 to -3, -5 to -7, -9, and -10). C2 domain-containing protein families that are related to synaptotagmins include: (1) transmembrane proteins, such as: (1.1) ferlins that are involved in Ca\({}^{++}\)-mediated membrane fusion; (1.2) extended synaptotagmin-like proteins (intracellular membrane-associated eSyt1 and plasmalemmal eSyt2 and eSyt3); and (1.3) Ca\({}^{++}\)-binding, membrane-anchored, multiple C2-domain and transmembrane region proteins MCTP1 and MCTP2 that are encoded by 2 genes; as well as (2) soluble proteins, such as: (2.1) members of the Rim family of regulating synaptic membrane exocytosis proteins, scaffold proteins that contribute to synaptic vesicle exocytosis during short-term remodeling; (2.2) brain-specific peripheral membrane protein Munc13 that interacts with syntaxin, a component of the exocytic synaptic core complex, and RIM1; (2.3) synaptotagmin-related proteins; and (2.4) trans-Golgi network membrane-associated B/K proteins (or SytB/K) that are expressed in the brain and kidney.
- 104.
The Rab27a effector SLP2 is recruited after melanophilin for the correct peripheral distribution of melanosomes in melanocytes. In melanocytes, Rab27 binds to melanosomes and recruits melanophilin and myosin-5a to transfer melanosomes from microtubules to actin filaments. Whereas C-terminal tandem C2 domain-containing protein rabphilin as well as rabphilin-3A-like without C2 domain protein NoC2 (or Rph3aL) that is involved in exocytosis in endo- and exocrine cells interact with all Rab27 isoforms as well as members of group-3 (Rab3 set) and group-8 (Rab8a set) Rab GTPases, Rim1 interacts with Rab3 isoforms, Rab26, and Rab37, as well as Rab10 (group-8 Rab GTPases), and Rim2 with Rab3 isoforms and Rab8a [870].
- 105.
Numerous adaptors support activation of PI3K using in particular signals emanating from cargos that concentrate into the vesicle.
- 106.
As the PI(3)P concentration reaches a certain threshold, Mon1b is recruited to the vesicular membrane, where it removes Rab5GEF agent.
- 107.
Protein Mon1b also interacts with the HoPS complex, hence recruiting and activating Rab7 GTPase.
- 108.
Mannose 6-phosphate binds 2 transmembrane proteins: cation-dependent (cdM6PR) and -independent (ciM6PR or IGF2R).
- 109.
A.k.a. 47-kDa tail-interacting protein (TIP47).
- 110.
The retromer also participates in mannose 6-phosphate receptor transport to the trans-Golgi network. It involves Rab7 + late endosomes.
- 111.
Three cytosolic complexes — the Biogenesis of lysosome-related organelles complexes — (BLOC1–BLOC3), like clathrin-associated adaptor proteic complex AP3 and homotypic fusion and vacuole protein sorting (HoPS) complex, mediate vesicular transport during the genesis of lysosome-related organelles. The AP3 and HoPS complexes participate in vesicular transport in the endosomal–lysosomal compartment. Active HoPS complex that binds phosphoinositides and vacuolar SNARE proteins couples Rab GTPase activation and SNARE complex assembly during membrane fusion. Biogenesis of lysosome-related organelles complex BLOC1 is a ubiquitous, multisubunit, proteic complex required for the formation of specialized organelles of the endosomal–lysosomal network, such as melanosomes and platelet dense granules. The complex includes Cappuccino, dysbindin, Muted homolog, pallidin, snapin, and BLOC1 subunits BLOC1S1 to BLOC1S3 (or BLOS1–BLOS3). The Hermansky-Pudlak syndrome (HPS) is a set of autosomal recessive disorders characterized by deficiencies in lysosome-related organelles, such as melanosomes and platelet-dense granules, hence oculocutaneous albinism, prolonged bleeding, and mild ceroid lipofuscinosis. This disease results from gene mutations. Eight genes can be involved, which encode subunits of vesicular transport complexes, such as AP3 and HoPS complexes. In addition to β3a subunit of the AP3 complex that mediates signal-dependent transfer of integral membrane proteins to lysosomes and related organelles, other implicated genes encode HPS1, HPS3, and HPS4 proteins. These proteins exist in soluble and membrane-associated forms. Subtype HPS4, but not HPS3, associates with HPS1 in the BLOC3 complex, the simplest of the above-mentioned complexes [882].
- 112.
A.k.a. 160-kDa Akt (PKB) substrate (AS160).
- 113.
For example, cardiomyocytes express neither Rac2 nor Rac3.
- 114.
Agent Rac2 is involved in both enzyme release from granules and NADPH oxidase activation during phagocytosis to kill bacteria.
- 115.
In stretched neonatal rat cardiac fibroblasts, Rac1 activity returns to its original level after 4 h, whereas RhoA remains at a high level of activity until the end of the prolonged stretch period (24 h) [890]. Mechanical stretch initially causes a moderate decrease in AGT gene expression and a secondary increase from 8 h. Small RhoA GTPase mediates both the stretch-induced inhibition of ATG gene at 4 h and subsequent upregulation of ATG gene expression at 24 h. Integrin-β1 enables acute (2 and 15 min) stretch-induced Rac1 activation, but represses RhoA activity. Unlike Rac1, RhoA mediates hypertrophy in the myocardium via its effector RoCK kinase.
- 116.
Concentration of Rad GPTase rises in the skeletal muscle of a subset of patients with type-2 diabetes mellitus.
- 117.
A.k.a. CCN (CTGF, CyR61 [cysteine-rich angiogenic inducer 61], NOv [nephroblastoma overexpressed]) family member-2 (CCN2). In cultured neonatal cardiomyocytes, Rad overexpression suppresses both basal and transforming growth factor-β1-induced CTGF expression. Factor TGFβ1 actually strongly fosters CTGF expression via SMAD3 in many cell types, particularly cardiac myocytes and fibroblasts. However, SMAD3 phosphorylation and SMAD reporter activity is not disturbed when Rad activity is altered.
- 118.
Ras-related Ral simian leukemia viral proto-oncogene product homolog.
- 119.
Phospholipase-D1 is also activated by small GTPase CDC42, Rac1, and RhoA as well as PKC-α.
- 120.
Exocyst complex connects exocytic vesicles to specific docking sites on the plasma membrane.
- 121.
A.k.a. AF6 and cytoskeleton-anchoring mixed lineage leukemia translocated protein MLLT4.
- 122.
Adaptor RIAM binds to activated Rap1 to cause adhesion of T lymphocytes to the extracellular matrix. It also connects to VASP proteins and actin-elongation factor profilin.
- 123.
Telomere maintenance by telomerase, tankyrase, and telomeric proteins is necessary for normal cell life, as its disregulation can accelerate aging and cause cancer. Tankyrase-1, a member of the polyADPribose polymerase (PARP) family of enzymes is also called TRF1-interacting ankyrin-related ADPribose polymerase TIN1 and PARP5a. It binds to and adpribosylates TRF1 protein. The shelterin hexamer is composed of 2 double-stranded telomeric DNA-binding repeat-binding factors TRF1 and TRF2, a single-stranded telomeric DNA-binding protein Protection of telomeres POT1, TRF1-interacting nuclear factors TIN2, adrenocortical dysplasia homolog (ACD), a binding partner of POT1 (a.k.a. TIN2 (two)-interacting protein TINT1, POT1-interacting protein PIP1, POT1 and TIN2 organizing protein [PTOP], and TINT1/PTOP/PIP1 protein TPP1), and TRF2-interacting factor Rap1. Component TRF2 recruits and stabilizes the shelterin complex to telomeres. Component ACD regulates both POT1 telomere localization and telosome assembly via TIN2 binding. It prevents telomerase-mediated telomere elongation.
- 124.
In the absence of shelterin, factors of DNA-damage checkpoints and repair would process chromosome ends as double-strand breaks.
- 125.
A.k.a. telomeric repeat-binding factor TRF2-interacting protein TRF2IP1 and telomeric repeat-binding factor TeRF2-interacting protein (TeRF2IP).
- 126.
The HDR process can create undesirable telomeric sister chromatid exchange when NHEJ process is abrogated. Protein TRF2 inhibits HDR, as it tethers Rap1 to telomeres [910].
- 127.
Telomerase adds DNA sequence repeats (TTAGGG) to the 3′ end of DNA strands in telomeres. Telomere, a region of repeated nucleotides, contains non-coding DNA material and prevents DNA loss from chromosome ends.
- 128.
In addition to their IκB substrates, IKK1 and IKK2 phosphorylate P65NFκB, P53, β-catenin, and 23-kDa synaptosomal-associated protein SNAP23.
- 129.
Human platelets produce at significant levels Rap1b and Rap2b, the amount of Rap1b being about 10-fold higher than that of Rap2b [915].
- 130.
Proteins of the RAS superfamily consist of 6 β-sheets and 5 α-helices interconnected by a set of 10 loops. They have RasGEF and RasGAP-binding interfaces. Inactive (RasGDP) and active (RasGTP) conformations differ by switch-1 and -2 regions.
- 131.
The regulation of the non-muscle and smooth muscle Factin cytoskeleton involves phosphorylation of the regulatory myosin light chains, leading to the formation of actin filaments.
- 132.
Aliases hRas and kRas stand for proto-oncogene products associated with Harvey and Kirsten sarcoma virus-associated oncogenes, respectively.
- 133.
In a CAAX sequence, C means Cys, A is usually, but not always, an aliphatic amino acid, and X is any amino acid. Farnesylpyrophosphate is is added to Cys of the CAAX motif of Ras by farnesyltransferase via a stable thioether linkage [920]. The CAAX motif is sequentially processed to undergo prenylation, proteolysis, and then methylation by 3 enzymes: rate-limiting, cytosolic farnesyltransferase, endoplasmic reticulum RAS-converting enzyme-1, and endoplasmic reticulum isoprenylcysteine carboxylmethyltransferase. The 2 first reactions are irreversible, whereas the third is reversible.
- 134.
Palmitate, a saturated (acyl) fatty acid, is added to 1 or 2 Cys residues immediately upstream of the CAAX sequence of Ras GTPases by one or more transmembrane palmitoyl acyltransferases, such as the complex made of DHHC domain-containing DHHC9 and 16-kDa Golgi body-associated protein GPC16 and other Ras-processing, DHHC motif-containing palmitoyl acyltransferases, via a labile thioester bond [920].
- 135.
The AAX amino acids of the CAAX sequence are substrates for the peptidase Ras-converting enzyme RCE1. After proteolysis, the carboxyl group of the new C-terminal prenylcysteine of Ras is methylesterified by isoprenylcysteine carboxylmethyltransferase (ICMT) [920].
- 136.
In particular, protein kinase-C phosphorylates kRas4b (Ser181) [920]. Small RalA GTPase is phosphorylated (Ser194) by Aurora-A kinase.
- 137.
The Gly–Pro peptidyl-prolyl bond of hRas (at position 178–179) undergoes cis–trans isomerization processed by 12-kDa FK506-binding protein (FKBP12) [920].
- 138.
Agents hRas, nRas, and kRas4b can be mono- and diubiquitinated on Lys residues by the ligase rabaptin-5-associated exchange factor for Rab5 (RabEx5), or RabGEF1 [920].
- 139.
Residue Cys118 in all Ras isoforms operates as a redox indicator that can be nitrosylated when exposed to nitric oxide [920].
- 140.
Agent kRas4b is not palmitoylated. It possesses a Lys-rich domain that complements farnesylation.
- 141.
The Ras GTPases – hRas, nRas, and kRas – have isoform-specific effects, in particular due to their different location at the inner surface of the plasma membrane and possibly in the Golgi body membranes, both sites that are involved in Ras signaling. Small GTPases hRas and nRas are palmitoylated and can be located in the plasma membrane and Golgi body membranes. Small kRas GTPase localizes to the plasma membrane. A deacylation and reacylation (depalmitoylation and repalmitoylation) cycle maintains the specific intracellular distribution [921]. Moreover, the kinetics of hRas and nRas GTPase trafficking are different. Small hRas GTPase, stimulated by growth factors, is rapidly and transiently activated at the plasma membrane, whereas it has a delayed and sustained activation at the Golgi body membranes. Small GTPase nRas is activated sooner than hRas at the Golgi body. Inhibition of palmitoylation blocks Ras activation. De-palmitoylation redistributes farnesylated Ras in required membranes. Repalmitoylation, which occurs at the Golgi body, enables Golgi membrane anchorage. Protein Ras is then redirected to the plasma membrane by exocytosis.
- 142.
Enzyme PLCε cleaves PIP2 into IP3 and DAG that release Ca\({}^{++}\) and activates PKC, respectively.
- 143.
Agent TIAM1 is involved in Ras-associated tumorigenesis.
- 144.
Proteins RIN1 and RASSF are Ras-interacting proteins that act as tumor suppressors. The RASSF family includes 8 identified members (RASSF1–RASSF8) that have pro-apoptotic function.
- 145.
Selective ablation of Ras loci in mouse embryonic fibroblasts has shown that each Ras is capable of sustaining proliferation of these cells in culture in the absence of the other two [924]. However, kRas are more efficient to cause cell proliferation than hRas or nRas. Other Ras-like small GTPases, even constitutively active types, cannot compensate for the absence of Ras proteins. The PI3K–PTen–PKB and RalGEF–Ral pathways, either alone or combined, do not launch cell proliferation or migration of Ras-less cells, although they are able to cooperate with the Raf–MAP2K–ERK axis [924]. Moreover, Ras signaling does not induce cell proliferation via the expression of cyclin-D, as CcnD1–CDK4 and CcnE–CDK2 complexes have normal concentrations in Ras-less mouse embryonic fibroblasts, but remain inactive. Signaling from Ras initiates the cell cycle by activating pre-existing CcnD–CDK4, CcnD–CDK6, or CcnE–CDK2 complexes rather than by inducing expression of cyclins-D [924].
- 146.
Protein rRas differs from the other members of the Ras family. It contains a proline-rich SH3 domain binding site. It can be phosphorylated by EPH receptors and Src. Both the SH3 binding site and phosphorylation regulate rRas activity.
- 147.
Differences in nanocompartmentation between hRras and kRras may partly explain isoform specific differences in MAPK signaling. Kinase cRaf is, indeed, selectively retained in kRas, but not in hRas nanoclusters.
- 148.
Prenylation is the attachment of lipid chains to proteins to enable their attachment to cell membranes. Bound fatty acids, such as palmitate or myristate, serve to anchor proteins to inner or outer face of a given membrane.
- 149.
Unlike hRas and nRas, kRas localizes exclusively to the plasma membrane, where it recruits cRaf.
- 150.
- 151.
Aldosterone augments ENaC density and activity in kidneys [925]. ENaC channels connect to PI(3,4,5)P3 that raises the channel activity.
- 152.
Alias ARFTS is here used rather than the usual abbreviation ARF to avoid confusion with small GTPase ARF (adpribosylation factor).
- 153.
The RA domain is a conserved motif defined by sequence homologies between 2 Ras effectors: (1) Ral guanosine nucleotide-exchange factor (RalGDS) involved in Ras-induced transformation and (2) Afadin (Aggressive acute lymphocytic leukemia ALL1 fusion partner from chromosome-6 [AF6] or myeloid–lymphoid or mixed lineage leukemia translocated to 4 [MLLT4]) implicated in intercellular adhesion.
- 154.
A.k.a. regulator for cell adhesion and polarization enriched in lymphoocytes (RAPL) and novel Ras effector NoRE1.
- 155.
Originally termed hRAS1 cluster HRC1.
- 156.
Early thymocyte progenitors initiate rearrangements of the TCR locus that enables production of functional preTCR complexes. The latter primes thymocyte proliferation and differentiation. T lymphocytes then express mature TCR complexes.
- 157.
Adaptor GRB2 then binds phosphorylated receptors and adaptors, such as plasmalemmal linker for activated T cells (LAT). Adaptor LAT is a substrate for the kinase 70-kDa ζ-associated protein (ZAP70). It acts also as a scaffold for various signaling complexes, as it interacts with phospholipase-Cγ1 and lymphocyte cytosolic protein LCP2 (or SH2 domain-containing phosphoprotein of 76 kDa [SLP76]) via GRB2-like adaptors such as GRB2-related adaptor protein GRAP2.
- 158.
Like LAT, Vav1 forms proteic complexes with ZAP70 kinase and LCP2 adaptor in activated T lymphocytes. In T lymphocytes, Vav1 is the major type, whereas in B lymphocytes, Vav1 and Vav2 have redundant functions.
- 159.
Tuberous sclerosis is a genetic disease caused by mutations in either the Tsc1 or Tsc2 genes.
- 160.
Small Rho GTPases regulate bundling of actin filaments into stress fibers and formation of focal adhesion complexes. Activation of Rac GTPases causes actin polymerization to form lamellipodia (broad cytoplasmic extensions) during cell migration (Vol. 2 – Chap. 6. Cell Motility), whereas activated CDC42 stimulates actin polymerization in filopodia (long and thin cytoplasmic extensions).
- 161.
Growth factors and cytokines activate Rho GTPases via interactions with guanine nucleotide-exchange factors, GTPase-activating proteins, guanine nucleotide-dissociation inhibitors, and GDI dissociation molecules.
- 162.
Integrins can both directly activate and enhance growth factor activation of small GTPases Rac and CDC42 via their recruitment to the plasma membrane. Integrins contribute to activation of phosphatidylinositol 3-kinase, possibly via focal adhesion kinase and CDC42, and promote polymerization and organization of actin filaments.
- 163.
A.k.a. ERM-binding phosphoprotein EBP50 and SLC9a3r1.
- 164.
At least 3 different isoforms of Ser/Thr protein kinase PKN exist: PKNα (a.k.a. PKN1, PAK1, and PRK1), PKNβ (a.k.a. PKN3 and PAK3), and PKNγ (a.k.a. PKN2, PAK2, and PRK2).
- 165.
Small Rho GTPases isoforms RhoX are also called ArhX as they were called low-density lipoprotein receptor adaptor proteins. The ARH2 gene encodes low-density lipoprotein receptor adaptor protein-1. Acronym ARH stands for autosomal recessive hypercholesterolemia. In fact, low-density lipoprotein receptor (LDLR) plays a pivotal role in cholesterol metabolism. Defects in LDLR or apolipoprotein-B, the proteic component of LDL particles that binds the LDL receptor, elevate circulating LDL–cholesterol levels. Genetic mutations in ARH gene on chromosome 1 cause autosomal recessive hypercholesterolemia (ARH).
- 166.
Phosphorylation prevents its association with the plasma membrane, enhances its affinity for RhoGDIs, and protects it from degradation [945]. Other kinases, such as FAK, Src, and PKG, indirectly regulate RhoA activity.
- 167.
Phosphatase PTPn11 dephosphorylates FAK for focal adhesion turnover during migration and RoCK2 to stimulate its binding to RhoA.
- 168.
Crosstalk between RhoA and other small GTPases is mediated via RhoGAPs and GEFs. Protein RasA1 interacts with Deleted in liver cancer protein DLC1 and then inhibits GAP activity of DLC1 in focal adhesions to increase RhoA activity. Small GTPases Rac or CDC42 can interfere with Rho via P21-activated-kinases and RhoGEFs [945]. Kinase PAK1 binds to RhoGEF1 to block the signaling from thrombin receptors to RhoA. Kinase PAK4 interacts with and phosphorylates RhoGEF2 to inhibit stress fiber formation. Protein BCR serves both as a RhoGEF and RacGAP.
- 169.
The activity of many proteins is implicated in metastasis: (1) constituents of the extracellular matrix and regulators of the matrix assembly and (2) components of the cytoskeleton and regulators of its dynamics: collagen-1α2 and -3α1, fibronectin, a ligand for integrins, calcium-binding matrix Gla proteins, biglycans, keratan sulfate proteoglycan fibromodulin, a collagen fibril formation regulator, tPA, angiopoietin-1, lysozyme-M, cathepsin-S, ERK1, α-catenin, α-actinin, calmodulin, actin-sequestering thymosin-β4, and other cytoplasmic and nuclear actin-related proteins, as well as eukaryotic initiation and elongation factors, endoplasmic reticulum-membrane translocators, etc.
- 170.
GTPase CDC42 binds and activates WASP proteins that, in turn, activate the actin-nucleating ARP2–ARP3 complex. It also binds and activates Brain-specific angiogenesis inhibitor 1-associated protein BAIAP2 (or 53-kDa insulin receptor substrate protein [IRSP53]) that recruits WASP family protein Enabled homolog EnaH to the filopodial tip and protects elongating actin filaments from capping.
- 171.
A.k.a. TC10-like (TCL) GTPase, TC10βL (TC10β long), ArhJ, RasL7B, and RhoI.
- 172.
A.k.a. teratocarcinoma-associated protein TC10 or RasL7a.
- 173.
Most RHO superfamily members undergo geranylgeranylation. However, RhoQ is farnesylated and palmitoylated. These post-translational modifications allow RhoQ to connect to membrane rafts.
- 174.
A.k.a. Miro-1 or ArhT1.
- 175.
A.k.a. Miro-2.
- 176.
A.k.a. WRCH1, as it is a Wnt-responsive CDC42 homolog.
- 177.
A.k.a. CHP (CDC42 homologous protein), ArhV, and WRCH2 (Wnt-responsive CDC42 homolog-2.
- 178.
A.k.a. Rem and Ges.
- 179.
Mouse ortholog Kir.
- 180.
A.k.a. Ras-related associated with diabetes (RRad) and Rem3.
- 181.
Membrane tethering of Ras GTPases generally requires a C-terminal isoprenyl group that is post-translationally added on cysteine–alanine–alanine–any amino acid (CAAX) motif. In some RAS hyperfamily members, this CAAX motif is replaced by a CXC or CC motif. Internal palmitoylation or a C-terminal cluster of basic amino acids yields another source [988]. Certain unusual Ras-related GTPases (Rad, Kir, and Gem) that lack a CAAX or similar site contain a cysteine residue that can be targeted for isoprenylation.
- 182.
The CAAX motif corresponds to the Cys–Ala–Ala-any amino acid sequence that attaches prenyl groups to anchor selected cellular membranes.
- 183.
Among common features in human tumors, elevated Ras signaling can originate from overexpression of upstream receptor tyrosine kinases or mutations in RAS genes. Signaling pathways downstream from small GTPases Ras prime many Ras effectors, such as bRaf and PI3K kinases that stimulate cell proliferation and repress apoptosis, respectively. Members of the Ras-association domain family (RASSF) operate as tumor suppressors that enhance apoptosis; silencing of RASSF genes may promote tumor cell survival. Mutations in genes that encode Ras effectors, such as bRaf and PI3K, also contribute to cancer.
- 184.
A.k.a. RIC-like expressed in many tissues and type-1 Ras-like without CAAX motif.
- 185.
Rho guanine nucleotide-exchange factors (RhoGEF) has Diffuse B-cell lymphoma (DBL) homology (DH) and pleckstrin homology (PH) domains that catalyze GDP–GTP exchange. Other domains are specific to each member. On the other hand, the regulator of G-protein signaling (RGS) domain acts as a GTPase-activating protein (GAP). Some GEFs such as 180-kDa protein downstream of CRK-related proteins contain 2 DOCK homology domains.
- 186.
For example, Vav1 activates RhoA, RhoG, Rac1, and CDC42. T-cell-lymphoma invasion and metastasis TIAM1 targets Rac1, Rac2, and Rac3. Triple functional domain protein (TRIO) stimilates Rac, RhoA, and RhoG [831].
- 187.
The Sec7 family is based on homology of ArfGEF catalytic domains to yeast ArfGEF Sec7p protein.
- 188.
Brefeldin-A, a fungal toxin, blocks secretion by preventing the assembly of coat protein components onto donor membranes. It is an uncompetitive inhibitor of the exchange reaction that binds to an ARFGDP–ArfGEF complex.
- 189.
The name cytohesin originates from observation that cytohesin-1 activates β2-integrin-mediated adhesion.
- 190.
Cytohesin-1 is also called pleckstrin homology, Sec7, and coiled-coil domain-containing protein PSCD1 and ARF nucleotide-binding site opener ARNO2. Cytohesin-2 is also named ARF nucleotide-binding site opener (ARNO), PSCD2, Sec7-containing protein-like substance Sec7l, and CTS18. Cytohesin-3 is also termed ARNO3, PSCD3, or general receptor for phosphoinositides RasGRP1. Cytohesin-4 is also labeled as ARNO4 and PSCD4. The Sec7 domain contains a guanine nucleotide-exchange motif, a coiled-coil region involved in homodimerization, and a PH domain that interacts with phospholipids.
- 191.
Vesicles with an AP1-containing coat are mainly located in the trans-Golgi network. Coat adaptor complex consists of AP1β1, -γ1, -μ1, and -σ1 subunits (adaptins). It links clathrin to the membrane of vesicles. Three classes of coated transport vesicles can be defined: (1) CoP2-coated vesicles that bud from the endoplasmic reticulum; (2) CoP1-coated vesicle coats that assemble onto cisternae of the Golgi body and intermediate compartment between the endoplasmic reticulum and Golgi body; and (3) clathrin-coated vesicles that contain AP1 and AP2 adaptor complexes that arise from the trans-Golgi network and the plasma membrane. Whereas adaptor-related proteic complex AP1 is related to Golgi processing, AP2 adaptor complex that is also formed by 4 adaptins (β2, -γ2, -μ2, and -σ2 adaptins) works on the plasma membrane to internalize cargo in clathrin-mediated endocytosis.
- 192.
Agent ARF6, which localizes to the plasma membrane and endosomes, regulates the endosome–plasma membrane transfer and remodeling of the actin cytoskeleton at the cell cortex. At synapses, the submembrane cytoskeleton controls the number and dynamics of neurotransmitter receptors on the postsynaptic membrane, thereby modulating synaptic transmission efficiency.
- 193.
Adaptor DLg4 that anchors synaptic proteins directly and indirectly binds neuroligin, 2 ionotropic glutamate receptors (Nmethyl Daspartate [NMDAGlu receptors (NMDAR)] and α-amino 3-hydroxy 5-methyl 4-isoxazolepropionic acid [AMPAGlu receptors (AMPAR)] receptors), and voltage-gated potassium channels KV1.2, KV1.4, and KV1.5. Homer-1 regulates group-1 metabotrophic glutamate receptors.
- 194.
A.k.a. actin crosslinking family member ACF7.
- 195.
In epithelia and endothelia, apical tight junctions create a barrier for ions and solutes, whereas cadherin-mediated adherens junctions link actin networks of neighboring cells.
- 196.
A.k.a. CRK SH3-binding GEF (C3G).
- 197.
A.k.a. PDZ domain-containing GEFs (PDZGEF1 and PDZGEF2). Alias PDZ combines the first letters of 3 proteins: postsynaptic density protein PSD95, or DLg4, Disc large homolog DLg1, and zonula occludens protein ZO1. ¡they are also called Ras/Rap1-association GEFs (RAGEF1 and RAGEF2).
- 198.
A.k.a. cAMP-dependent guanine nucleotide-exchange factor CNRasGEF in addition to PDZGEF1 and RAGEF1.
- 199.
A.k.a. atrophin-1-interacting protein-3 and brain-specific angiogenesis inhibitor (BAI1)-associated protein BAIAP1 (or BAP1).
- 200.
Hence the name synaptic scaffolding molecule (SSscM).
- 201.
A.k.a. cAMP-dependent cAMPGEF1 and 2 and exchange protein directly activated by cAMP EPAC1 and EPAC2. Upon cAMP binding, EPACs undergo a conformational change that relieves auto-inhibition. In addition, cAMP enables translocation of EPACs from the cytosol to the plasma membrane.
- 202.
Phosphatidic acid also enables recruitment of DOCK2 RacGEF at the leading edge of migrating neutrophils and SOS RasGEF to cell adhesion-free membrane regions.
- 203.
A.k.a. Rap1-Binding protein K-Rev1 interaction trapped gene product KRIT1. Protein CCM1 forms a family with cerebral cavernous malformation proteins CCM2 and CCM3 (a.k.a. programmed cell death protein PDCD10).
- 204.
A.k.a. mixed lineage leukemia translocated protein MLLT4.
- 205.
A.k.a. guanine nucleotide-exchange factor for Rap1 (GFR) and mRas (rRas3)-regulated GEF (MRGEF).
- 206.
Proteins RasGRP1 and RasGRP2 are also named CalDAGGEF2 and CalDAGGEF1, respectively.
- 207.
A.k.a. small-molecular-weight, GTP-binding, guanine nucleotide (GDP)-dissociation stimulator (SMGGDS).
- 208.
A.k.a. SH2 domain-containing protein SH2D3b, novel SH2-containing protein NSP2, and AND34.
- 209.
A.k.a. small monomeric GTPases, GTP–GDP dissociation stimulator SMGGDS.
- 210.
Proteins of the RASGRP category have calcium-binding EF hand sequences and diacylglycerol-binding domain [1023].
- 211.
Stimulation of TCRs causes phosphorylation of Rho- and RacGEF Vav1. The latter activates PLCγ1 that synthesizes diacylglycerol. Diacylglycerol then binds to and activates RasGRP1 in leukocytes and neurons. Protein RasGRP1 can thus be activated by both PKC-dependent and -independent axes. In addition, the Vav1–PLCγ1 pathway promotes actin-dependent translocation of RasGRP1 to the plasma membrane. Besides, PKC can activate ERK1 and ERK2 enzymes. Therefore, 3 pathways leads to the MAPK module: (1) TCR–Vav–PLC–DAG–PKCθ–MAPK; (2) TCR–Vav–PLC–DAG–PKC–RAsGRP1–Ras–MAPK; and (3) TCR–Vav–PLC–DAG–RAsGRP1–Ras–MAPK.
- 212.
Kinase Src is a common effector of both G-protein-coupled receptors and receptor Tyr kinases.
- 213.
Agents RasGRF1 and RasGRF2 possess 2 pleckstrin homology (PH) regions, a coiled-coil motif, a Ca\({}^{++}\)–calmodulin binding ilimaquinone (IQ) domain, a DBL homology (DH) sequence for both homodimerization and catalysis of the GDP–GTP exchange on Rac1, and the prototypical CDC25 Ras exchange domain [1025].
- 214.
Agent RasGRP1 is highly expressed in neurons of the forebrain (prosencephalon), whereas RasGRP2 is particularly highly produced in the striatum [926].
- 215.
A.k.a. DOCK180, a mammalian ortholog of Caenorhabditis elegans protein Ced5.
- 216.
A.k.a. modifier of cell adhesion (MOCA) and presenilin-binding protein (PBP).
- 217.
Other association with members of the CAS family, such as the CAS-CRK and CAS-Src complexes, are implicated in cell processes that involve the regulation of the actin cytoskeleton (cell adhesion, migration, proliferation, and survival).
- 218.
A.k.a. human enhancer of filamentation HEF1.
- 219.
Adaptor BCAR1, also called CRK-associated substrate (CAS or P130CAS), is a binding partner and potent enhancer of Src kinase activity. Kinases of the SRC family (e.g., Fyn, Src, and Yes) mediate integrin-dependent CAS phosphorylation.
- 220.
Neither novel Ser peptidase (alias NSP), nor nuclear structure protein (also NSP).
- 221.
A.k.a. SH2 domain-containing protein SH2D3a.
- 222.
A.k.a. breast cancer anti-estrogen resistance BCAR3, SH2D3b, SHEP2, and AND34 (from thymic “AND” T-cell receptor in transgenic mice).
- 223.
A.k.a. SH2D3c, CRK-associated substrate and human enhancer of filamentation (CAS–HEF1)-associated signal transducer [CHAT] and SH2 domain-containing EPH receptor-binding protein SHEP1. Protein NSP3 binds both EPH receptors such as EPHb2 as well as rRas and Rap1a, but neither hRas nor RalA, thereby linking activated EPH receptors to small Ras GTPases [1039].
- 224.
A.k.a. neural precursor cell expressed, developmentally down-regulated NEDD9 and human enhancer of filamentation HEF1.
- 225.
Neuroendocrine-specific proteins, or reticulons, are indicators of neuroendocrine tumor cells of the lung.
- 226.
Reticulons interact with proteins involved in vesicle formation and fusion, such as SNAREs and SNAPs; they act as regulators of Rab-controlled intracellular transport. Both Rtn1c and Rtn4a are inhibitors of BCLxL apoptosis inhibitor; Rtn1c also inhibits BCL2. All reticulons interact with membrane-bound aspartyl peptidase BACE1 (β-site APP-cleaving enzyme-1), a δ-secretase that cleaves amyloid precursor protein into β-amyloid peptide; they prevent access of BACE1 to APP substrate.
- 227.
These 3 isoforms share only the C-terminal reticulon homology domain. Protein NOGoC N-terminus is encoded by a transcript generated from a different promoter to those of primary transcripts of N termini of NOGoA and NOGoB subtypes [1040].
- 228.
Nine detected transcripts are generated from 4 reticulon genes (Rtn1a–Rtn1b, Rtn2a–Rtn2c, Rtn3a1, and Rtn4a, Rtn4b1–Rtn4b2, Rtn4c). The common C-terminus encodes the reticulon homology (RH) domain, whereas N-termini are specific for each paralog. Different isoforms of reticulon-3 exists (Rtn3a1–RTN3a4); in addition, Rtn3a3 and Rtn3a4 yields 2 subtypes (Rtn3a3a–Rtn3a3b and Rtn3a4a–Rtn3a4b).
- 229.
Shortest NOGo isoform (Rtn4c).
- 230.
Both NOGR1 and PIRb interact with 3 NOGo isoforms. Receptor NOGR1 binds also to the growth inhibitor myelin-associated glycoprotein (MAG), or siglec-4A, and oligodendrocyte myelin glycoprotein (OMGP) [1040]. Myelin-associated glycoprotein, its soluble cleaved form, and NOGoA are glia-derived inhibitors that yield a non-permissive environment for elongating nerve fibers via RhoA activation and Rac1 repression. The RhoA effector RoCK phosphorylates LIMK1 kinase, which, in turn, phosphorylates cofilin, there leading to actin depolymerization. Protein MAG binds with higher affinity to NOGo receptor-2 (NOGR2), or reticulon-4 receptor-like protein (Rtn4RL). Other proteins compete with NOGoA for binding to NOGR1 receptor.
- 231.
Integrin signaling also induces formation of a complex with BCAR1, adaptor CRK, and GEF DOCK1, that is required for membrane ruffling in cell migration.
- 232.
G12/13-coupled receptors include lysophosphatidic acid, lysophosphatidylcholine (GPR132), sphingosine 1-phosphate, thromboxane-A2, peptidase-activated (PAR1), muscarinic M3, serotonin, and α1-adrenergic receptors.
- 233.
The RH domain of RhoGEF1, RhoGEF11, and RhoGEF12 that requires further 60 amino acids in addition to the conserved 120 amino acid RGS box to confer GAP activity is also named RGS-like (RGL or RGSL) and RhoGEF RGS (rgRGS) domain.
- 234.
The DH domain catalyzes nucleotide-exchange. The PH domain differs according to the RhoGEF type with a function that facilitates interaction with Rho or localizes the GEF via connection to specific polyphosphoinositides.
- 235.
A.k.a. Cloned-out of library proteins COOL2 and COOL1, respectively, or P90COOL2 and P85COOL1, with P50COOL1 splice variant. They are also called P21-activated kinase-interacting exchange factors α- and β-PIX, respectively).
- 236.
A.k.a. GDP–GTP exchange factor collybistin.
- 237.
GABARAP: GABAA receptor-associated protein; P130: IP3-binding, PLCδ1-related, catalytically inactive protein, an inhibitor of binding of γ2 subunit of GABAA receptor to GABARAP.
- 238.
A.k.a. osteosarcoma protein Ost.
- 239.
Lipid modification of GABARAP is necessary for the suppression of RhoGEF14-3 activity.
- 240.
A.k.a. Duo, kalirin, and Huntingtin-associated protein-interacting protein (HAPIP).
- 241.
A.k.a. dynamin-binding protein (DnmBP) and Tuba according to the tradition of naming large synaptic proteins as musical instruments.
- 242.
A.k.a. Wiskott-Aldrich protein-interacting protein (WIP)-related protein WIRe.
- 243.
A.k.a. corticosteroid and regional expression protein-16 homolog (CR16).
- 244.
A.k.a. P53-inducible protein PIR121.
- 245.
A.k.a. 90-kDa SH3 adaptor protein interacting with NCK (SPIN90) and Wiskott-Aldrich syndrome protein (WASP)-interacting SH3-domain protein (WISH).
- 246.
A.k.a. 190-kDa RhoA-binding protein P190RhoGEF and Ras-specific nucleotide-exchange factor CDC25.
- 247.
A.k.a. GEF720, synectin-binding RhoA exchange factor [Syx], and transcript highly enriched in cortex and hippocampus (TECH).
- 248.
A.k.a. InaD-like protein (InadL).
- 249.
Angiomotin that is expressed in the endothelial cells from capillaries to larger vessels in the placenta regulates junctions between endothelial cells and cell migration. Angiomotin binds and internalizes angiostatin, a circulating inhibitor of angiogenesis [1060]. It localizes to the leading edge of migrating endothelial cells and stimulates cell motility. Conversely, angiostatin binds angiomotin on the cell surface to preclude the migration of angiomotin-expressing cells. Angiomotin not only controls cell motility, but also intervenes in the assembly of junctions between endothelial cells. Angiomotin colocalizes with scaffold ZO1 in tight junctions [1061], the presence of ZO1 depending on PlekHg5 protein. Paracellular permeability is reduced by p80 and p130 angiomotin isoforms.
- 250.
A.k.a. Protein associated with Lin-7 PALS1.
- 251.
The human genome generates more than 70 RhoGEFs with tissue-restricted expression (but only 22 Rho GTPases). Among RhoGEFs, 25 to 30 are RhoAGEFs. Except RhoGEF30 (obscurin), the expression of which is restricted to the heart and striated muscle, RhoAGEFs do not exhibit a tissue-specific pattern. A group of 13 RhoAGEF mRNAs is characterized by a moderate and heterogeneous expression according to the artery type (e.g., RasGRF1 [P190RhoGEF] is produced at high levels in the aorta and at low levels in mesenteric and pulmonary arteries).
- 252.
I.e., Scambio, RhoGEF1, RhoGEF2, RhoGEF3, RhoGEF5, RhoGEF11, RhoGEF12, RhoGEF13, RhoGEF14, RhoGEF15, RhoGEF17, RhoGEF18, RhoGEF19, RhoGEF21, RhoGEF23, RhoGEF24, RhoGEF25, RhoGEF27, RhoGEF31, ABR, BCR, Vav1–Vav3, RasGRF1 (p190RhoGEF), FARP1, and PlekHg5.
- 253.
The name “Son of sevenless” derives from the fact that SOS operates downstream of the sevenless gene in Drosophila melanogaster.
- 254.
As Vav protein was the sixth discovered oncogene, it was named “Vav”, the sixth letter of the Hebrew alphabet.
- 255.
Mice deficient in Vav3 exhibit tachycardia and hypertension.
- 256.
A.k.a. P67PhOx (phagocyte oxidase), a 67-kDa neutrophil oxidase used as a subunit of NADPH oxidase.
- 257.
A.k.a. 76-kDa SH2 domain-containing leukocyte protein (SLP76).
- 258.
A.k.a. Enx1. It pertains to the Polycomb group of transcriptional repressors.
- 259.
Coatomer CoP2 operates in anterograde transport from endoplasmic reticulum to the cis-Golgi network.
- 260.
A.k.a. centaurin-α1 and PIP3BP.
- 261.
A.k.a. centaurin-α2.
- 262.
Nucleolin is involved in the synthesis and maturation of ribosomes.
- 263.
A.k.a. Narginine dibasic convertase (NRD).
- 264.
This complex is made of large adaptin-δ3 and -β3, medium adaptin-μ3, and small adaptin-σ3.
- 265.
A.k.a. GIT2, paxillin kinase linker (PKL) and COOL-associated and Tyr-phosphorylated protein CAT2. Alias PKL also stands for liver (L)- and red blood cell (R)-type pyruvate kinase (other aliases PKLR, PKR, and RPK) that also interacts with paxillin, Rac-activated kinase PAK1, and RhoGEF6, in addition to kinesin KIF23 [251].
- 266.
A.k.a. GIT1 and COOL-associated and Tyr-phosphorylated protein CAT1.
- 267.
Stimulation by growth factors such as EGF that provokes PI(3,4,5)P3 formation causes ARAP3 translocation to the plasma membrane [1080]. Stimulation by PDGF that also induces PI(3,4,5)P3 synthesis leads to ARAP3 translocation to lamellipodia.
- 268.
A.k.a. CAS ligand with multiple SH3 domains (CMS). Adaptor CD2AP binds to BCAR1, SRC family kinases, phosphatidylinositol 3-kinase, and GRB2 adaptor. Cluster of differentiation CD2 receptor (a.k.a. LFA2 and LFA3) is a cell-adhesion molecule on the surface of T lymphocytes and natural killer cells.
- 269.
A.k.a. Development and differentiation-enhancing factors DDEF1 and DDEF2, as well as centaurin-β4 and -β3, respectively.
- 270.
A.k.a. Development and differentiation-enhancing factor-like protein DDEFL1, ACAP4, and Centβ6.
- 271.
A.k.a. endoplasmic reticulum retention signal-containing protein ERD2.
- 272.
A.k.a. 85-kDa CBL-interacting protein CIn85 for epidermal growth factor receptor internalization.
- 273.
A.k.a. proline-rich motif in EH-domain-containing protein POB1.
- 274.
Hence its name amphiphysin-2M.
- 275.
Members of the BCAR–CAS family include human enhancer of filamentation HEF1 (a.k.a. CASl and neural precursor cell expressed, developmentally down-regulated protein NEDD9) mostly found in lymphocytes, lung, and breast, and embryonal Fyn-associated substrate (EFS or Src-interacting protein SIN) in embryonic tissues. Non-receptor protein Tyr kinases Src, FAK1, FAK2, and Abl phosphorylate BCAR1. Adaptor BCAR1 allows CRK to interact with effectors that activate Rac1 GTPase. The BCAR1–CRK–Rac1 signaling leads to JNK activation [1038]. In addition, CRK shuttles from BCAR1–CRK complexes to CRK–GAB, CRK–CBL, or CRK–IRS1 complexes in response to certain signals.
- 276.
Protein TBC1D6 is also called growth hormone-regulated TBC protein GRTP1; TBC1D11 RabGAP1; and TBC1D18 RabGAP1L.
- 277.
A.k.a. SH3 and multiple ankyrin repeat domain-containing protein SHAnk2.
- 278.
A.k.a. SHAnk3 protein.
- 279.
A.k.a. bromodomain-containing protein BrD4. The Bromodomain is involved in chromatin targeting.
- 280.
A.k.a. ring finger and WD repeat domain-containing protein RFWD2.
- 281.
A.k.a. synaptic Ras GTPase-activating protein SynGAP1.
- 282.
A.k.a. inositol (1,3,4,5)-tetrakisphosphate-binding protein (GAP1IP4BP).
- 283.
A.k.a. calcium-promoted Ras inactivator (CaPRI).
- 284.
A.k.a. RasAL and GAP1-like protein.
- 285.
A.k.a. RasA5 and synaptic GTPase-activating protein SynGAP1.
- 286.
Acronym nGAP is also used for neuronal growth-associated proteins, such as stathmin, stathmin-like-2, and growth-associated protein GAP43 that are targets of neurotrophin. They are also related to small GTPase. Activated Rac and, to a lesser extent, CDC42 downstream from epidermal growth factor lead to stathmin phosphorylation, hence inhibition of stathmin-induced destabilization of microtubules.
- 287.
A.k.a. Merlin, a portmanteau for moesin-ezrin-radixin-like protein, and schwannomin.
- 288.
A.k.a. RAS P21 protein activator-1, SynGAP1, and P120GAP.
- 289.
A.k.a. dihydropyrimidinase-like protein DPysL2.
- 290.
A.k.a. ASK1-interacting protein AIP1, an alias to avoid for the sake of disambiguation.
- 291.
A.k.a. ArhGAP1 and CDC42GAP.
- 292.
A.k.a. ArhGAP1, CDC42GAP, and P50RhoGAP.
- 293.
Activators of CDK5, short-lived CDK5r1 (or 35-kDa protein P35) and the regulatory subunit-2 (CDK5r2 (or P39), complex CDK5 similarly to cyclins. The CDK5r1–CDK5 complex phosphorylates: (1) structural proteins, such as constituents of intermediate neurofilaments (nestin and neurofilament heavy and middle chains) and actin filaments, as well as cytoskeleton-regulatory proteins such as microtubule-associated proteins Tau, and (2) proteins involved in neurotransmitter release, such as synapsin-1 and syntaxin-binding protein-1.
- 294.
A.k.a. P190bRhoGAP, P190b, ArhGAP5, and growth factor independent GFI2.
- 295.
A.k.a. P190aRhoGAP (or simply P190RhoGAP), P190a, ArhGAP35, and glucocorticoid receptor DNA-binding factor GRF1.
- 296.
Agents RhoGAP7, RhoGAP37, and RhoGAP38 are also called StAR-related lipid transfer domain-containing proteins StARD12, StARD13, and StARD8, respectively, steroidogenic acute regulator (StAR)-related lipid transfer (StART) domain-containing proteins (StARTGAP1–StARTGAP3), and Deleted in liver cancer proteins (DLC1–DLC3).
- 297.
A.k.a. ArhGAP7, P122RhoGAP, and adaptor for Rho and PLC P122ARP. Alias DLC1 is also used for dynein light chain, which is better termed dynein light chain LC8-type-1 DynLL1 for disambiguation.
- 298.
Not dynein light chain-2 that should be termed dynein light chain LC8-type DynLL2 for the sake of disambiguation.
- 299.
A.k.a. GTPase regulator associated with focal adhesion kinase (GRAF) and oligophrenin1-like protein (OphnL1).
- 300.
This repellant molecule prevents axon crossing through the midline of the brain and spinal cord.
- 301.
A.k.a. formin-binding protein FnBP2.
- 302.
A.k.a. mental disorder-associated GAP (MeGAP) and WAVE-associated RacGAP protein (WRP). Members of the WASP family of scaffold proteins such as WAVE participate in actin reorganization, especially during cell migration.
- 303.
The plasma membrane of epithelial cells is asymmetrically organized into apical and basolateral regions. These 2 regions are separated by tight junctions (Vol. 1 – Chap. 7. Plasma Membrane) that encircle cells and yield lateral contact with neighboring cells. Cell polarity structures are regulated via phosphorylation and Rho GTPases.
- 304.
Angiomotin supports migration of endothelial cells triggered by growth factors. The motin family of proteins comprises 3 members: angiomotin (AMot), angiomotin-like-1 (AMotL1), and angiomotin-like-2 (AMotL2). Alternative splicing in endothelial cells and other cell types raises the molecular diversity within this protein family.
- 305.
I.e., membrane palmitoylated protein-5; a.k.a. protein associated with Lin-7 (PALS1).
- 306.
A.k.a. PALS1-associated tight junction protein (PATJ).
- 307.
A.k.a. sodium–hydrogen antiporter-3 regulator NHERF1 and SLC9a3r1.
- 308.
A.k.a. bone marrow stromal cell antigen BSt2 and CD317.
- 309.
A.k.a. SH3 domain-binding protein SH3BP1 (or 3BP1).
- 310.
A.k.a. GTP-binding protein overexpressed in skeletal muscle (GEM)-interacting protein (GMIP).
- 311.
A.k.a. GTP-binding mitogen-induced T-cell protein and kinase-inducible Ras-like protein (KIR).
- 312.
The Breakpoint cluster region (BCR) gene is involved in chromosomal translocations that cause the development of chronic myeloid leukemia and a subset of acute lymphoblastic leukemia.
- 313.
A.k.a. male germ-cell RacGAP (MGCRacGAP), IDGAP, and Homo sapiens cytokinesis defect protein HSCYK4.
- 314.
Cytokinesis is related to the assembly and constriction of an actomyosin ring at the cell equator. It requires regulated changes in protein phosphorylation. Cyclin-dependent kinase CDK1 on the one hand and Polo-like kinase PlK1 and Aurora-B on the other regulate cytokinesis negatively and positively, respectively. Polo-like kinase PlK1 phosphorylates RacGAP1 that can then assemble with ECT2.
- 315.
A.k.a. Ral-interacting protein (RIP or RIP1) and 76-kDa Ral-interacting protein (RlIP76).
- 316.
Agent RalGDS and RalGDS-like protein are activators of both RalA and RalB GTPases.
- 317.
A.k.a. Lowe oculocerebrorenal syndrom (LOCR).
- 318.
Subunit Neutrophil P47PhOx (phagocytic oxidase) is also called neutrophil cytosol factor-1 and neutrophil NADPH oxidase factor-1. The NADPH oxidase complex of phagocytes is constituted by membrane-associated flavocytochrome-B559 and 4 cytosolic components: P40PhOx, P47PhOx, P67PhOx, and Rac GTPase.
- 319.
Syndecan-4 tethering to synectin increases synectin binding to RhoGDI1 and synectin enhances RhoGDI1 affinity for RhoG.
- 320.
Monomeric Rho GTPases that are prenylated act at membranes. Newly synthesized small GTPases of the RHO superfamily are geranylgeranylated and then post-translationally modified by the peptidase RAS-converting enzyme RCE1 and by isoprenylcysteine carboxyl methyltransferase (ICMT) at the cytoplasmic face of the endoplasmic reticulum. After geranylgeranylation by geranylgeranyl transferase, Rho proteins associate with RhoGDIs [1128].
- 321.
Small Rho GTPases that are neither bound to RhoGDIs nor associated with membranes are destroyed. Free prenylated cytosolic Rho GTPases are unstable; they are rapidly degraded by the proteasome.
- 322.
The rate of cycling of the RhoGDI–Rho complex between the cytosol and target membrane can be regulated by post-translational modifications on both Rho GTPase and RhoGDI protein.
- 323.
Protein RhoGDI2 associates with several Rho GTPases in vitro, but with significantly lower affinity than RhoGDI1. Many of these interactions are not detected in vivo [1128].
- 324.
The interaction of TNFRSF16 with RhoGDIs is enhanced by myelin-derived proteins, such as myelin-associated glycoprotein (MAG), or siglec-4a, and reticulon-4, also called reticulon-5, neuroendocrine-specific protein-C homolog (NSP or NSPcL), and neurite outgrowth inhibitor (NOGo).
- 325.
A.k.a. RhoGDIα and aplysia Ras-related homolog GDI ArhGDIα.
- 326.
A.k.a. epithelial and endothelial Tyr kinase (ETK).
- 327.
Diacylglycerol kinase phosphorylates diacylglycerol to produce phosphatidic acid that stimulates PI(4)P5K1. Lipid PI(4,5)P2 may cause the release of Rac from RhoGDI1 protein. Protein Rac can then be activated by GEFs.
- 328.
A.k.a. RhoGDIβ, developmentally regulated GDI (D4GDI), and lymphocyte GDI (LyGDI). Expression of RhoGDI2 in hematopoietic cell lines is modulated by cell fate. Cell division and differentiation indeed augment RhoGDI2 production.
- 329.
A.k.a. RhoGDIγ.
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Thiriet, M. (2013). Guanosine Triphosphatases and Their Regulators. In: Intracellular Signaling Mediators in the Circulatory and Ventilatory Systems. Biomathematical and Biomechanical Modeling of the Circulatory and Ventilatory Systems, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4370-4_9
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