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The PDGFR Receptor Family

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Receptor Tyrosine Kinases: Family and Subfamilies

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Abbreviations

17-AAG:

17-allylamino-17demethoxygeldanamycin

a.a.:

Amino acid

AGM:

Aorta–gonad–mesonephros

AHCYL1:

Adenosylhomocysteinase-like 1

Akt:

v-Akt murine thymoma viral oncogene homologue

AL:

Activation loop

ALL:

Acute lymphoblastic leukemias

ALSP:

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

AML:

Acute myeloid leukemia

AP1:

Activator protein 1

ATP:

Adenosine triphosphate

BARF1:

Epstein–Barr virus lytic-cycle early protein 1

Bcl-2:

B-cell lymphoma 2

Bcl-X(L):

B-cell lymphoma-extra large

BMM:

Bone marrow-derived macrophages

bp:

Base pairs

C/EBPα:

CCAAT-enhancer-binding protein alpha

C1P:

Ceramide-1 phosphate

cAMP:

Cyclic adenosine monophosphate

Caspase:

Cysteine-dependent aspartate-directed protease

Cbl:

Casitas B-lineage lymphoma

CCL12:

Chemokine (C-C motif) ligand

CCR:

C-C chemokine receptor

CD:

Cluster of differentiation

cDC:

Lymphoid-tissue resident or classical DC

Cdc42:

Cell division control protein 42 homologue

c-Fms:

McDonough feline sarcoma virus oncogene (v-Fms) homologue

c-Fos:

Finkel–Biskis–Jinkins murine osteogenic sarcoma virus oncogene (v-fos) homologue

CFU-GM:

Colony-forming unit–granulocyte–macrophage

CFU-M:

Colony-forming unit–macrophage

c-Kit:

Hardy–Zuckerman 4 feline sarcoma viral oncogene (v-Kit) homologue

CLP:

Common lymphoid progenitor

CML:

Chronic myeloid leukemia

CMP:

Common myeloid progenitor cells

CMT:

Charcot–Marie–Tooth disease

c-Myc:

(v-Myc) myelocytomatosis viral oncogene homologue

CNS:

Central nervous system

CSF:

Colony-stimulating factor

CSF-1:

Colony-stimulating factor-1

CSF-1R:

Colony-stimulating factor-1 receptor

CT:

Cytoplasmic tail

CX3CR1:

CX3C chemokine receptor 1

DAP12:

DNAX-activating protein of 12 kDa

DC:

Dendritic cells

DNMT1:

DNA methyl transferase 1

Dok-1:

Docking protein 1

DUSP:

Dual-specificity phosphatase

DUSP5:

Dual-specificity phosphatase 5

EBV:

Epstein–Barr virus

ECD:

Extracellular domain

Egr2:

Early growth response 2

EM:

Electron microscopy

EMT:

Epithelial–mesenchymal transition

EPS8L3:

Epidermal growth factor receptor pathway substrate 8 like 3

ERK1/2:

Extracellular signal-regulated kinases 1 and 2

ERα:

Estrogen receptor alpha

Ets:

E26 transformation specific

EWS:

Ewing sarcoma breakpoint region

FDMCs:

Follicular dendritic cell-induced monocytes

FIMP:

Fms-interacting protein

FIRE:

Fms-intronic regulatory element

FL:

FLT3 ligand

flk-2:

Fetal liver kinase 2

Flt3:

Fms-like tyrosine kinase 3

FUS/TLS:

Fused in sarcoma/translocated in sarcoma

Fyn:

Proto-oncogene tyrosine-protein kinase Fyn

Gab2:

Grb2-associated-binding protein 2

GCL:

Globoid cell leukodystrophy

GEF:

Guanine nucleotide exchange factor

GFAP:

Glial fibrillary acidic protein

GFP:

Green fluorescent protein

GM:

Geldanamycin

GM-CSF:

Granulocyte–macrophage CSF

GMP:

Granulocyte–macrophage progenitor

GMP:

Granulocyte–macrophage progenitors

GnRH:

Gonadotropin-releasing hormone

Grb2:

Growth factor receptor-bound protein 2

GSKβ:

Glycogen synthase kinase 3 beta

HA:

Herbimycin A

Hck:

Tyrosine-protein kinase HCK

HDLS:

Hereditary diffuse leukoencephalopathy with axonal spheroids

HIV-1:

Human immunodeficiency virus type 1

HLA:

Human leukocyte antigen

HMGXB3:

HMG-box domain containing 3

HSC:

Hematopoietic stem cells

Ifi20:

Interferon-inducible P204 protein

IFNγ:

Interferon γ

Ig:

Immunoglobulin

IL-3:

Interleukin-3

IL-34:

Interleukin-34

IL-4:

Interleukin-4

IPC:

Type 1 interferon-producing cells

IRSp53:

Insulin receptor tyrosine kinase substrate p53

ISC:

Intestinal stem cells

ITD:

Internal tandem duplications

ITIM:

Immunoreceptor tyrosine-based inhibitory motifs

JAK:

Janus kinase

JDP2:

Jun dimerization protein 2

JM:

Juxtamembrane

JM-B:

JM-binding motif

JMD:

Juxtamembrane domain

JM-S:

JM switch motif

JM-Z:

Zipper segment

JNK:

c-Jun N-terminal kinase

JunB:

Transcription factor jun-B

KA:

Kainic acid

KC:

Keratinocyte chemoattractant

K d :

Dissociation constant

LC:

Langerhans cells

Ldlr  −/− :

Low-density lipoprotein receptor null

LEF:

Lymphoid enhancer-binding factor

LH:

Luteinizing hormone

LILRB:

Leukocyte Ig-like receptor B

LIMK:

LIM domain kinase

LMPP:

Lymphoid primed multipotent progenitors

Lnk:

Lnk adaptor protein

LPS:

Lipopolysaccharide

LSK:

lin-kit+sca-1+

LT-HSC:

Long-term hematopoietic stem cells

Lyn:

Tyrosine-protein kinase Lyn

MAP-kinase:

Mitogen-activated protein kinase

MCP-1:

Monocyte chemoattractant protein 1

M-CSF:

Macrophage colony-stimulating factor

MDP:

Macrophage–DC progenitors

MDS:

Myelodysplastic syndrome

MEK:

Mitogen-activated protein kinase kinase

MEP:

Megakaryocyte/erythrocyte progenitors

MIP-2:

Macrophage inflammatory protein-2

miR:

Micro RNA

Mitf:

Microphthalmia-associated transcription factor

MKP:

MAP-kinase phosphatase

MKP-1:

Mitogen-activated protein kinase phosphatase-1 (also known as DUSP-1)

Mo:

Monocytes

Mona:

Monocytic adaptor

MPP:

Multipotent progenitor

mTOR:

Mammalian target of rapamycin

MΦ:

Macrophages

NBCn1:

Na/HCO3 co-transporter 1

N-CoR:

Nuclear receptor corepressor

NFAT:

Nuclear factor of activated T cells

NFkB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NPC:

Neural progenitor cells

OC:

Osteoclast

p38:

p38 Mitogen-activated protein kinase

PA:

Plasminogen activator

PAX5:

Paired box protein 5

PC:

Paneth cells

pDC:

Plasmacytoid DC

PDGF:

Platelet-derived growth factor

PDGF:

Platelet-derived growth factor

PGE2:

Prostaglandin E2

PI3K:

Phosphatidylinositol 3-kinase

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PIP3:

Phosphatidylinositol 3,4,5-trisphosphate

PIR-B:

Paired Ig-like receptor B

PKCζ:

Protein kinase Ca-dependent zeta

PLC:

Phospholipase C

PLC:

Phospholipase C

PLD2:

Phospholipase D

POLD:

Pigmented orthochromatic leukodystrophy

PP2A:

Serine–threonine phosphatase 2A

Pro-B:

Progenitors of B cells

Pro-NK:

Progenitors of natural killer cells

Pro-T:

Progenitors of T cells

PSTPIP2:

Proline–serine–threonine (PEST)–phosphatase-interacting protein 2

PTB:

Phosphotyrosine-binding domains

PTK:

Protein-tyrosine kinase

PTPN12:

Protein-tyrosine phosphatase nonreceptor type 12

PTPϕ:

Nonreceptor protein-tyrosine phosphatase phi

PU.1:

Transcription factor PU.1

Pyk2:

Protein-tyrosine kinase 2 beta

Rac:

Ras-related C3 botulinum toxin substrate

RANKL:

Receptor activator of nuclear factor κB

Ras:

Rat sarcoma small GTPase

RBM6:

RNA-binding motif 6

RCC:

Renal clear cell carcinoma

Rho:

Rho small GTPase

Rho U/Wrch:

Wnt-1-responsive Cdc42 homologue, Rho family GTPase

RIP:

Regulated intramembrane proteolysis

RPTP-ζ:

Receptor protein-tyrosine phosphatase-zeta

RSK2:

Ribosomal S6 kinase 2

RTK:

Receptor tyrosine kinase

RTK:

Receptor tyrosine kinase

Runx1:

Runt-related transcription factor 1

RV FV3:

Ranavirus frog virus 3

S100A4:

S100 family Ca2+-binding protein A4

SAXS:

Small-angle X-ray scattering

SCF:

Stem cell factor

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SFK:

Src family kinases

SH2:

Src homology 2 domain

SH3BP2:

SH3 domain-binding protein 2

Shc:

Src homology 2 domain containing

SHIP:

SH2-containing inositol phosphatase

Shp2:

SH2 domain protein-tyrosine phosphatase 2

SIRPα:

Signal regulatory protein alpha

SIV:

Simian immunodeficiency virus

SKAP55R:

Src kinase-associated phosphoprotein of 55 kDa (SKAP55)-related adaptor protein

SLAP:

Src-like adaptor protein

SLAP2:

Src-like adaptor protein 2

SLP-76:

SH2 domain-containing leukocyte protein-76

SM-FeSV:

Susan McDonough strain of feline sarcoma virus

Snord11B:

Small nucleolar RNA CD box 11B

Socs1:

Suppressor of cytokine signaling 1

Sos:

Son of sevenless

Sp1/3:

Transcription factors Sp1 and Sp3

Src:

Rous sarcoma virus oncogenic tyrosine kinase homologue

STAP-2:

Signal-transducing adaptor protein 2

STAT:

Signal transducer and activator of transcription

Syk:

Spleen tyrosine kinase

T reg:

T regulatory cells

TACE:

TNFα-converting enzyme (also known as ADAM-17)

TAMs:

Tumor-associated macrophages

Tbx3:

T-box transcription factor 3

TCF:

T-cell-specific, HMG-box transcription factor

Tcptp:

T-cell protein-tyrosine phosphatase

TGFβ1:

Transforming growth factor beta 1

TLR:

Toll-like receptor

TRAF6:

TNF receptor-associated factor 6

TRAP:

Tartrate-resistant acid phosphatase

TREM2:

Triggering receptor expressed on myeloid cells 2

Vac14:

Vac14 homologue

Vav:

Vav oncogene

VDR:

Vitamin D receptor

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor 2.

WASP:

Wiskott–Aldrich syndrome protein

WAVE2:

WASP-family verprolin-homologous protein-2

Zp3-Cre:

Zona pellucida 3 promoter-driven Cre recombinase

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Acknowledgements

Section 10.1

We thank Dr. Cristina Caescu for critically reviewing the manuscript. We thank Drs. Jamie Rossjohn, Savas Savvides, Carsten Schubert, Melissa Starovasnik, and Andrew Wilks for permission to reproduce their high-resolution figures. This work was supported by NIH grants PO1 CA100324 and CA 32551 (to ERS), K01AR 054486 (to VC), and 5P30-CA13330 (a cancer center grant to the Albert Einstein College of Medicine).

Section 10.2

We thank Dr. Violeta Chitu for critically reviewing the manuscript. We thank Dr. James Griffith and Dr. Savas Savvides for permission to reproduce their high-resolution figures. This work was supported by NIH grants PO1 CA100324 and CA 32551 (to ERS) and 5P30-CA13330 (a cancer center grant to the Albert Einstein College of Medicine).

Section 10.4

Ingegärd Schiller is thanked for valuable help in the preparation of this manuscript.

Receptor at a glance: CSF-1R (human)

Chromosome location

5q32

Gene size (bp)

60,077

Intron/exon numbers

21/22

Amino acid number

972

kDa

Mr 130 (the immature, high mannose-containing form)

Mr 165 (the mature, N-glycosylated form)

Posttranslational modifications

Glycosylation, phosphorylation, ubiquitination

Domains

ECD (D1–D5), TM, ICD (JM, KD, IK, CT)

Ligands

CSF-1, IL-34

Known dimerizing partners

CSF-1R

Pathways activated

MAPK, PI3K, Rac, Rho, JAK/STAT

Tissues expressed

Hematopoietic stem cells and myeloid progenitors (e.g., CFU-GM, CFU-M), monocytes, tissue macrophages, microglia, osteoclasts, dendritic, Kupffer and Langerhans cells, neuronal subsets, neural progenitors, mammary epithelial cells, Paneth cells, renal proximal tubule epithelial cells, trophoblasts, oocytes

Human diseases

Activating CSF-1R mutations in myeloid malignancies, including acute megakaryoblastic leukemia, AML, CML

Inactivating mutations in ALSP

Knockout mouse phenotype

Late embryonic/early postnatal lethality. Osteopetrosis, toothlessness, growth impairment, neurological and reproductive defects

Receptor at a glance: FLT3 (human)

Chromosome location

13q12.2 (minus strand)

Gene size (bp)

96,982

Intron/exon numbers

23/24

mRNA size (5′, ORF, 3′)

3.7 kb (5′ 700 bp; ORF 2979 bp, 3′ 21 bp)

Amino acid number

993

KDa

Mr 130 (the immature, high mannose-containing form)

Mr 155/160 (the mature, N-glycosylated form)

Posttranslational modifications

Glycosylation, phosphorylation, ubiquitination

Domains

ECD (D1-D5), TM, ICD (JM, KD, IK, CT)

Ligands

FL

Known dimerizing partners

FLT3

Pathways activated

RAS/RAF/MAPK, PI3K/AKT/mTOR

Tissues expressed

Hematopoietic stem cells and early committed progenitors, such as lin-kit+sca-1+ (LSK) bone marrow cells and lin-AA4.1+ fetal liver cells, some B lymphocyte subsets, with lower expression on monocytes; placenta, gonads, and brain; blast cells from most ANLL and B-ALL

Human diseases

Activating FLT3 mutations in ALL, CML

Knockout mouse phenotype

Normal mature hematopoietic populations, deficient in primitive B-lymphoid progenitors. flt3  −/− HSCs have a reduced capacity to reconstitute T cells and myeloid cells

Receptor at a glancve: KIT

Chromosome location

4

Gene size (bp)

82,797 bp

Intron/exon numbers

20 introns, 21 exons

mRNA size (5′, ORF, 3′)

5 kbp

Amino acid number

976 amino acids

kDa

109,685 unglycosylated, 145 kDa as the mature, glycosylated form

Posttranslational modifications

glycosylation, phosphorylation, ubiquitylation

Domains

extracellular domain, transmembrane domain, juxtamembrane domain, kinase domain with kinase insert, carboxyterminal tail

Ligands

KITLG

Known dimerizing partners

 

Pathways activated

Ras/Erk pathway, PI3-kinase/Akt pathway, p38, Src family kinases, Cbl, Grb10, Gab10, Grb7, Crk, CrkL, SLAP, APS, Lnk, SHP1, SHP2

Tissues expressed

Mast cells, interstitial cells of Cajal, bone marrow stem cells, melanocytes, spermatogonia, oocytes

Human diseases

Mastocytosis, acute myeloid leukemia (in particular core factor binding leukemia), testicular seminoma, ovarian dysgerminoma, teratoma, small-cell lung cancer, gastrointestinal stroma tumors, malignant melanoma, allergy, asthma

Knockout mouse phenotype

Loss of pigment cells in skin, anemia, sterility, loss of intestinal cells of Cajal with resulting constipation, sometimes loss of hearing

Author information

Authors and Affiliations

  1. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, 10461, NY, USA

    Violeta Chitu, Cristina I. Caescu & E. Richard Stanley

  2. Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden

    Johan Lennartsson

  3. Lund Stem Cell Center, Lund University, Medicon Village, Lund, Sweden

    Lars Rönnstrand

  4. Translational Cancer Research, Lund University, Building 404:C3, Medicon Village, Lund, 22381, Sweden

    Lars Rönnstrand

  5. Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 595, 751 24, Uppsala, Sweden

    Carl-Henrik Heldin

Authors
  1. Violeta Chitu
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  2. Cristina I. Caescu
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  3. E. Richard Stanley
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  4. Johan Lennartsson
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  5. Lars Rönnstrand
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  6. Carl-Henrik Heldin
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Corresponding author

Correspondence to E. Richard Stanley .

Editor information

Editors and Affiliations

  1. School of Medicine and Public Health Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Rehovot, Israel

    Yosef Yarden

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Chitu, V., Caescu, C.I., Stanley, E.R., Lennartsson, J., Rönnstrand, L., Heldin, CH. (2015). The PDGFR Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_10

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