Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101607


Historical Background

GIPC1 was cloned and characterized independently by diverse research groups as GAIP (RGS19)-interacting protein C-terminus [GIPC] (De Vries et al. 1998), GLUT1 (SLC2A1) C-terminal binding protein [GLUT1CBP] (Bunn et al. 1999), Insulin-like growth factor-1 receptor (IGF1R)-interacting protein 1 [IIP1] (Ligensa et al. 2001), Neuropilin 1 (NRP1)-interacting protein [NIP] (Cai and Reed 1999), Semaphorin 4C (SEMA4C) cytoplasmic domain-associated protein 1 [SEMCAP1] (Wang et al. 1999), Syndecan 4 (SDC4)-interacting protein [Synectin] (Gao et al. 2000), and Tax-interacting protein 2 [TIP2] (Rousset et al. 1998).

GIPC2 (Kirikoshi and Katoh 2002) and GIPC3 (Saitoh et al. 2002) were cloned and characterized as novel GIPC family members that are related to GIPC1. GIPC3 was then characterized as the causative gene for autosomal recessive deafness as DFNB15, DFNB72, and DFNB95 (Charizopoulou et al. 2011; Rehman et al. 2011).

Xenopus Kermit 1 interacting with Frizzled 3 (Xfz3) (Tan et al. 2001) and Xenopus Kermit 2 interacting with Igf1r (Wu et al. 2006) are the orthologs of human GIPC2 and GIPC1, respectively (Reviewed in Katoh 2013).

The GIPC Family

The human GIPC gene family includes: the GIPC1 gene at human chromosome 19p13.12, the GIPC2 gene at human chromosome 1p31.1, and the GIPC3 gene at human chromosome 19p13.3 (Reviewed in Katoh 2013). GIPC1 and GIPC2 are more closely related to each other than they are to GIPC3. GIPC family proteins share a common domain architecture consisting of a GIPC homology 1 (GH1) domain, a PDZ domain, and a GH2 domain (Fig. 1).
GIPC, Fig. 1

GIPC family. (a) Schematic representation of GIPC proteins. GIPC family proteins consist of a GIPC homology 1 (GH1) domain, a PDZ domain, and a GH2 domain. (b) Phylogenetic analyses of GIPC family proteins. GIPC1 and GIPC2 are more closely related. (c) Alignment of human GIPC family proteins. The amino-acid position is shown on both sides of the alignment. Conserved amino acids are indicated by an asterisk below the alignment. The GH1 domain (pink box), the PDZ domain (blue box), and the GH2 domain (yellow box) are well conserved among GIPC family proteins

Physiological Functions of GIPC Proteins

GIPC family members are adaptor proteins that assemble transmembrane proteins, cytoplasmic signaling regulators, and the motor protein Myosin VI (MYO6) (Fig. 2). The PDZ domain of GIPC1 is involved in interactions with transmembrane proteins, such as adrenergic receptor β1 (ADRB1), dopamine receptor D2 (DRD2), DRD3, IGF1R, Integrin α5, NRP1, NTRK1 (TrkA), SDC4, SEMA4C, TGFβ receptor type III (TGFβR3), and Van Gogh-like 2 (VANGL2) (Reviewed in Katoh 2013), as well as with the cytoplasmic signaling components APPL1 (Schenck et al. 2008), PLEKHG5 (Liu and Horowitz 2006), and RGS19 (De Vries et al. 1998). The regions around the GH1 and PDZ domains of GIPC1 are necessary for the dimerization of GIPC1, whereas the region around the GH2 domain of GIPC1 is necessary for its interaction with MYO6 (Reed et al. 2005).
GIPC, Fig. 2

Physiological function of GIPC1. GIPC1 interacts with receptor tyrosine kinases (RTKs) [IGF1R and NTRK1], G protein-coupled receptors (GPCRs) [ADRB1, DRD2 and LHCGR], single-span transmembrane (TM) proteins [Integrin α5, NRP1, TGFβR3, etc.], the tetra-span TM protein [VANGL2], cytosolic signaling regulators [APPL1, PLEKHG5, and RGS19], and the MYO6 motor protein. Because MYO6 moves along actin filaments from the plus (barbed) end near the plasma membrane to the minus (pointed) end in the cytoplasm, the GIPC1-MYO6 complex is directly involved in early endosomal trafficking and signaling and is indirectly involved in the subsequent recycling of its cargoes

The GIPC1-MYO6 complex is involved in the endosomal trafficking of their cargoes because MYO6 is a motor protein that moves along actin filaments from the plus (barbed) ends to the minus (pointed) ends (Reviewed in Katoh 2013). For example, integrin α5β1 is trafficked to the early endosomes as a cargo of the GIPC1-MYO6 complex as a result of an interaction between GIPC1 and the integrin α5 subunit and is then sorted for recycling to the plasma membrane. GIPC1 is required for the integrin recycling during cell migration, angiogenesis, and cytokinesis (Reviewed in Katoh 2013).

GIPC1 recruits RGS19 that functions as a GTPase-activating protein (GAP) for Gαi and modulates signaling through G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) (Fig. 2). The dopamine receptors DRD2 and DRD3 are Gi- or Go-associated GPCRs that inhibit the formation of cyclic AMP (cAMP) and activate the RAS-ERK signaling cascade. GIPC1 interacting with DRD2/3 and RGS19 eased the restriction of the cAMP route but failed to inhibit the RAS-ERK signaling cascade in HEK 293 cells (Jeanneteau et al. 2004; Arango-Lievano et al. 2016). NTRK1 is a RTK that transduces NGF signals to the RAS-ERK and PI3K-AKT signaling cascades. GIPC1 interacting with NTRK1 and RGS19 inhibited the RAS-ERK signaling cascade, but not the PI3K-AKT signaling cascade in PC12 cells (Lou et al. 2001). The GIPC1-RGS19 complex regulates the formation of cAMP and RAS-ERK signaling in a cellular context-dependent manner.

GIPC1 recruits the endosomal scaffold proteins APPL1 and APPL2 to modulate signaling through RTK, such as IGF1R (Fig. 2). IGF1 binding to IGF1R induces their dimerization, autophosphorylation, and subsequent activation of the PI3K-AKT and RAS-ERK signaling cascades. Because APPL1 and APPL2 assemble AKT and GSK3β onto the endosomal signaling compartment (Schenck et al. 2008), GIPC1 interacting with IGF1R preferentially activates the PI3K-AKT signaling cascade in mouse embryonic stem cells, which is required for the specification of eye field cells (La Torre et al. 2015).

GIPC1 also recruits PLEKHG5 that functions as a guanine exchange factor (GEF) for RhoA to activate the RhoA-ROCK signaling cascade (Liu and Horowitz 2006). VEGF signaling through NRP1 and VEGFR2 receptors on endothelial cells plays a key role in angiogenesis (Pellet-Many et al. 2008). Although it remains unclear whether the GIPC1-mediated assembly of NRP1 and PLEKHG5 is involved in VEGF-induced RhoA activation, PLEKHG5 overexpression promoted the migration and tube formation of endothelial cells.

These facts indicate that GIPC1 regulates a variety of cellular processes, such as the endosomal trafficking of GIPC1-MYO6 cargoes, the endosomal signaling from GPCRs and RTKs, and the recycling of transmembrane proteins (Fig. 2).

Pathological Functions of GIPC Proteins

Germ-line homozygous mutations in the GIPC3 gene, including G46R, M88I, G94D, H170N, R189C, T221I, G256D, L262R, W301X, and A229GfsX10, occur in patients with autosomal recessive nonsyndromic deafness (Charizopoulou et al. 2011; Rehman et al. 2011; reviewed in Katoh 2013). In contrast, germ-line homozygous G115R mutations in the Gipc3 gene that occur in Black Swiss (BLSW) mice are subject to progressive hearing loss owing to a disorientated stereocilia bundle of sensory hair cells and degraded sensory neurons in the spiral ganglion (Charizopoulou et al. 2011). Because the MYO6 gene is also mutated in patients with autosomal recessive nonsyndromic deafness (Duman and Tekin 2012), the GIPC3-MYO6 complex might play a key role in the specification of ear field cells, as with GIPC1 in the specification of eye field cells as mentioned above.

The HBc protein derived from hepatitis B virus (HBV) (Razanskas and Sasnauskas 2010), the E6 protein derived from human papillomavirus type 18 (HPV-18) (Favre-Bonvin et al. 2005), and the Tax protein derived from human T-cell leukemia virus type 1 (HTLV-1) (Rousset et al. 1998) are viral proteins that interact with the PDZ domain of GIPC1. Because HBV and HPV-18 cause hepatocellular carcinoma and cervical cancer, respectively, the GIPC1-associated signaling dysregulation that is involved in chronic viral infection and subsequent carcinogenesis should be further investigated.

The dysregulation of GIPC1 expression has been reported in a variety of human cancers such as breast, cervical, ovarian, and pancreatic cancers (Reviewed in Katoh 2013). Because the anti-GIPC1 human monoclonal antibody was established from a patient with breast cancer, GIPC1 is a cancer-associated auto-antigen (Rudchenko et al. 2008). GIPC1 upregulation promotes the proliferation and survival of pancreatic cancer cells through the aberrant activation of IGF1R signaling (Muders et al. 2009), whereas E6-mediated GIPC1 downregulation contributes to the survival of HeLa cells through the inhibition of TGFβ signaling (Favre-Bonvin et al. 2005).


GIPC1, GIPC2, and GIPC3 consist of GH1, PDZ, and GH2 domains. The PDZ domain of GIPC1 is involved in interactions with (i) the transmembrane proteins ADRB1, DRD2, DRD3, IGF1R, Integrin α5, NRP1, NTRK1, SDC4, SEMA4C, TGFβR3, and VANGL2, (ii) the cytoplasmic signaling components APPL1, PLEKHG5, and RGS19, and (iii) the viral proteins HBc, E6, and Tax. The GH2 domain of GIPC1 is indispensable for its interaction with MYO6 but is dispensable for the dimerization of GIPC1. A variety of the transmembrane proteins and signaling components of early endosomes are trafficked along actin filaments as cargoes of the GIPC1-MYO6 complex. GIPC1 assembles GPCRs and RGS19 for the attenuation of Gαi signaling and also assembles RTKs and APPL1 for the preferential activation of PI3K-AKT signaling. GIPC1 is required for recycling and the cell-surface expression of IGF1R and TGFβR3, as well as integrin recycling during cell migration and cytokinesis. IGF1R signaling activation is involved in the proliferation of tumor cells with GIPC1 upregulation, whereas TGFβ signaling inhibition is involved in the survival of tumor cells with E6-mediated GIPC1 downregulation. Germ-line homozygous mutations in the GIPC3 or MYO6 genes cause nonsyndromic hearing loss. GIPC family members are involved in a variety of physiological processes such as endosomal trafficking and signaling and the recycling of transmembrane proteins during cellular migration and cytokinesis; whereas dysregulated GIPCs are involved in the pathogenesis of cancer and hereditary deafness.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Omics NetworkNational Cancer CenterTokyoJapan