Receptor tyrosine kinases

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Receptor tyrosine kinases (RTKs), a family of cell-surface receptors, which transduce signals to polypeptide and protein hormones, cytokines and growth factors are key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism, cell migration and cell cycle control [4,18,45]. In the human genome, 58 RTKs have been identified, which fall into 20 families [28].

All RTKs display an extracellular ligand binding domain, a single transmembrane helix, a cytoplasmic region containing the protein tyrosine kinase activity (occasionally split into two domains by an insertion, termed the kinase insertion), with juxta-membrane and C-terminal regulatory regions. Agonist binding to the extracellular domain evokes dimerization, and sometimes oligomerization, of RTKs (a small subset of RTKs forms multimers even in the absence of activating ligand). This leads to autophosphorylation in the tyrosine kinase domain in a trans orientation, serving as a site of assembly of protein complexes and stimulation of multiple signal transduction pathways, including phospholipase C-γ, mitogen-activated protein kinases and phosphatidylinositol 3-kinase [45].

RTKs are of widespread interest not only through physiological functions, but also as drug targets in many types of cancer and other disease states. Many diseases result from genetic changes or abnormalities that either alter the activity, abundance, cellular distribution and/or regulation of RTKs. Therefore, drugs that modify the dysregulated functions of these RTKs have been developed which fall into two categories. One group is often described as ‘biologicals’, which block the activation of RTKs directly or by chelating the cognate ligands, while the second are small molecules designed to inhibit the tyrosine kinase activity directly.

Type I RTKs: ErbB (epidermal growth factor) receptor family

Formerly known as: ErbB (epidermal growth factor) receptor family

Overview

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ErbB family receptors are Class I receptor tyrosine kinases [18]. ERBB2 (also known as HER-2 or NEU) appears to act as an essential partner for the other members of the family without itself being activated by a cognate ligand [19]. Ligands of the ErbB family of receptors are peptides, many of which are generated by proteolytic cleavage of cell-surface proteins. HER/ErbB is the viral counterpart to the receptor tyrosine kinase EGFR. All family members heterodimerize with each other to activate downstream signalling pathways and are aberrantly expressed in many cancers, particularly forms of breast cancer.

Receptors

EGFR (epidermal growth factor receptor) Show summary » More detailed page

HER2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) Show summary » More detailed page

HER3 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) Show summary » More detailed page

HER4 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4) Show summary » More detailed page

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Type II RTKs: Insulin receptor family

Formerly known as: Insulin receptor family

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The circulating peptide hormones insulin (INS, P01308) and the related insulin-like growth factors (IGF) activate Class II receptor tyrosine kinases [18], to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Exceptionally amongst the catalytic receptors, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post-translationally into two peptides, which then cross-link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post-translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably IRS1 (P35568), IRS2 (Q9Y4H2), SHC1 (P29353), GRB2 (P62993) and SOS1 (Q07889).

Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBP1-5, P08833, P18065, P17936, P22692, P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers.

Receptors

InsR (Insulin receptor) Show summary » More detailed page

IGF1R (Insulin-like growth factor I) Show summary » More detailed page

IRR (Insulin receptor-related receptor) Show summary » More detailed page

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Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family

Formerly known as: PDGF (platelet-derived growth factor) receptor family

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Type III RTKs include PDGFR, CSF-1R (Ems), Kit and FLT3, which function as homo- or heterodimers. Endogenous ligands of PDGF receptors are homo- or heterodimeric: PDGFA, PDGFB, VEGFE and PDGFD combine as homo- or heterodimers to activate homo- or heterodimeric PDGF receptors. SCF is a dimeric ligand for KIT. Ligands for CSF1R are either monomeric or dimeric glycoproteins, while the endogenous agonist for FLT3 is a homodimer.

Receptors

PDGFRα (platelet-derived growth factor receptor, alpha polypeptide) Show summary » More detailed page

PDGFRβ (platelet-derived growth factor receptor, beta polypeptide) Show summary » More detailed page

Kit (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) Show summary » More detailed page

CSFR (colony stimulating factor 1 receptor) Show summary » More detailed page

FLT3 (fms-related tyrosine kinase 3) Show summary » More detailed page

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Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family

Formerly known as: VEGF (vascular endothelial growth factor) receptor family

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VEGF receptors are homo- and heterodimeric proteins, which are characterized by seven Ig-like loops in their extracellular domains and a split kinase domain in the cytoplasmic region. They are key regulators of angiogenesis and lymphangiogenesis; as such, they have been the focus of drug discovery for conditions such as metastatic cancer. Splice variants of VEGFR1 and VEGFR2 generate truncated proteins limited to the extracellular domains, capable of homodimerisation and binding VEGF ligands as a soluble, non-signalling entity. Ligands at VEGF receptors are typically homodimeric. VEGFA (VEGFA, P15692) is able to activate VEGFR1 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. VEGFB (VEGFB, P49765) and placental growth factor activate VEGFR1 homodimers, while VEGFC (VEGFC, P49767) and VEGFD (FIGF, O43915) activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.

Receptors

VEGFR-1 (fms-related tyrosine kinase 1) Show summary » More detailed page

VEGFR-2 (kinase insert domain receptor (a type III receptor tyrosine kinase)) Show summary » More detailed page

VEGFR-3 (fms-related tyrosine kinase 4) Show summary » More detailed page

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Type V RTKs: FGF (fibroblast growth factor) receptor family

Formerly known as: FGF (fibroblast growth factor) receptor family

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Fibroblast growth factor (FGF) family receptors act as homo- and heterodimers, and are characterized by Ig-like loops in the extracellular domain, in which disulphide bridges may form across protein partners to allow the formation of covalent dimers which may be constitutively active. FGF receptors have been implicated in achondroplasia, angiogenesis and numerous congenital disorders. At least 22 members of the FGF gene family have been identified in the human genome [11]. Within this group, subfamilies of FGF may be divided into canonical, intracellular and hormone-like FGFs. FGF1-FGF10 have been identified to act through FGF receptors, while FGF11-14 appear to signal through intracellular targets. Other family members are less well characterized [46].

Receptors

FGFR1 (fibroblast growth factor receptor 1) Show summary » More detailed page

FGFR2 (fibroblast growth factor receptor 2) Show summary » More detailed page

FGFR3 (fibroblast growth factor receptor 3) Show summary » More detailed page

FGFR4 (fibroblast growth factor receptor 4) Show summary » More detailed page

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Type VI RTKs: PTK7/CCK4

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The PTK7 receptor is associated with polarization of epithelial cells and the development of neural structures. Sequence analysis suggests that the gene product is catalytically inactive as a protein kinase, although there is evidence for a role in Wnt signalling [39].

Receptors

CCK4 (protein tyrosine kinase 7) Show summary » More detailed page

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Type VII RTKs: Neurotrophin receptor/Trk family

Formerly known as: Neurotrophin receptor/Trk family

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The neurotrophin receptor family of RTKs include trkA, trkB and trkC (tropomyosin-related kinase) receptors, which respond to NGF, BDNF and neurotrophin-3, respectively. They are associated primarily with proliferative and migration effects in neural systems. Various isoforms of neurotrophin receptors exist, including truncated forms of trkB and trkC, which lack catalytic domains. p75(TNFRSF16, also known as nerve growth factor receptor), which has homologies with tumour necrosis factor receptors, lacks a tyrosine kinase domain, but can signal via ceramide release and nuclear factor κB (NF-κB) activation. Both trkA and trkB contain two leucine-rich regions and can exist in monomeric or dimeric forms.

Receptors

trkA (neurotrophic tyrosine kinase, receptor, type 1) Show summary » More detailed page

trkB (neurotrophic tyrosine kinase, receptor, type 2) Show summary » More detailed page

trkC (neurotrophic tyrosine kinase, receptor, type 3) Show summary » More detailed page

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Type VIII RTKs: ROR family

Formerly known as: ROR family and other RTKs

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Members of the ROR family (ENSFM00510000502747) appear to be activated by ligands complexing with other cell-surface proteins. Thus, ROR1 and ROR2 appear to be activated by Wnt-5a (WNT5A, P41221) binding to a Frizzled receptor thereby forming a cell-surface multiprotein complex [20].

Receptors

ROR1 (receptor tyrosine kinase-like orphan receptor 1) Show summary » More detailed page

ROR2 (receptor tyrosine kinase-like orphan receptor 2) Show summary » More detailed page

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Type IX RTKs: MuSK

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The muscle-specific kinase MuSK is associated with the formation and organisation of the neuromuscular junction from the skeletal muscle side. forms a complex with LRP4 (O75096) to activate MuSK [23].

Receptors

MuSK (muscle, skeletal, receptor tyrosine kinase) Show summary » More detailed page

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Type X RTKs: HGF (hepatocyte growth factor) receptor family

Formerly known as: HGF (hepatocyte growth factor) receptor family

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HGF receptors regulate maturation of the liver in the embryo, as well as having roles in the adult, for example, in the innate immune system. HGF is synthesized as a single gene product, which is post-translationally processed to yield a heterodimer linked by a disulphide bridge. The maturation of HGF is enhanced by a serine protease, HGF activating complex, and inhibited by HGF-inhibitor 1, a serine protease inhibitor. MST1, the ligand of RON, is two disulphide-linked peptide chains generated by proteolysis of a single gene product.

Receptors

Met (met proto-oncogene) Show summary » More detailed page

Ron (macrophage stimulating 1 receptor (c-met-related tyrosine kinase)) Show summary » More detailed page

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Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family

Formerly known as: TAM (or AXL) receptor family

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Members of this RTK family (ENSFM00500000269872) represented a novel structural motif, when sequenced. The ligands for this family, Gas6 (GAS6, Q14393) and protein S (PROS1, P07225), are secreted plasma proteins which undergo vitamin K-dependent post-translational modifications generating carboxyglutamate-rich domains which are able to bind to negatively-charged surfaces of apoptotic cells.

Receptors

Axl (AXL receptor tyrosine kinase) Show summary » More detailed page

Tyro3 (TYRO3 protein tyrosine kinase) Show summary » More detailed page

Mer (c-mer proto-oncogene tyrosine kinase) Show summary » More detailed page

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Type XII RTKs: TIE family of angiopoietin receptors

Formerly known as: TIE family of angiopoietin receptors

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The TIE family were initially associated with formation of blood vessels. Endogenous ligands are angiopoietin-1 (ANGPT1, Q15389), angiopoietin-2 (ANGPT2, O15123), and angiopoietin-4 (ANGPT4, Q9Y264). angiopoietin-2 (ANGPT2, O15123) appears to act as an endogenous antagonist of angiopoietin-1 function.

Receptors

TIE1 (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) Show summary » More detailed page

TIE2 (TEK tyrosine kinase, endothelial) Show summary » More detailed page

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Type XIII RTKs: Ephrin receptor family

Formerly known as: Ephrin receptor family

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Ephrin receptors (ENSFM00250000000121) are a family of 15 RTKs (the largest family of RTKs) with two identified subfamilies (EphA and EphB), which have a role in the regulation of neuronal development, cell migration, patterning and angiogenesis. Their ligands are membrane-associated proteins, thought to be glycosylphosphatidylinositol-linked for EphA (EFNA1 (EFNA1, P20827) , EFNA2 (EFNA2, O43921), EFNA3 (EFNA3, P52797), EFNA4 (EFNA4, P52798) and EFNA5 (EFNA5, P52803)) and 1TM proteins for Ephrin B (ENSFM00250000002014: EFNB1 (EFNB1, P98172), EFNB2 (EFNB2, P52799) and EFNB3 (EFNB3, Q15768)), although the relationship between ligands and receptors has been incompletely defined.

Receptors

EphA1 (EPH receptor A1) Show summary » More detailed page

EphA2 (EPH receptor A2) Show summary » More detailed page

EphA3 (EPH receptor A3) Show summary » More detailed page

EphA4 (EPH receptor A4) Show summary » More detailed page

EphA5 (EPH receptor A5) Show summary » More detailed page

EphA6 (EPH receptor A6) Show summary » More detailed page

EphA7 (EPH receptor A7) Show summary » More detailed page

EphA8 (EPH receptor A8) Show summary » More detailed page

EphA10 (EPH receptor A10) Show summary » More detailed page

EphB1 (EPH receptor B1) Show summary » More detailed page

EphB2 (EPH receptor B2) Show summary » More detailed page

EphB3 (EPH receptor B3) Show summary » More detailed page

EphB4 (EPH receptor B4) Show summary » More detailed page

EphB6 (EPH receptor B6) Show summary » More detailed page

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Type XIV RTKs: RET

Overview

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Ret proto-oncogene (Rearranged during transfection) is a transmembrane tyrosine kinase enzyme which is employed as a signalling partner for members of the GDNF family receptors (see…). Ligand-activated GFR appears to recruit Ret as a dimer, leading to activation of further intracellular signalling pathways. Ret appears to be involved in neural crest development, while mutations may be involved in multiple endocrine neoplasia, Hirschsprung’s disease, and medullary thyroid carcinoma.

Receptors

Ret (ret proto-oncogene) Show summary » More detailed page

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Type XV RTKs: RYK

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The ‘related to tyrosine kinase receptor’ (Ryk) is structurally atypical of the family of RTKs, particularly in the activation and ATP-binding domains. RYK has been suggested to lack kinase activity and appears to be involved, with FZD8, in the Wnt signalling system [39].

Receptors

RYK (receptor-like tyrosine kinase) Show summary » More detailed page

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Type XVI RTKs: DDR (collagen receptor) family

Formerly known as: DDR (collagen receptor) family

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Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are structurally-related membrane protein tyrosine kinases activated by collagen. Collagen is probably the most abundant protein in man, with at least 29 families of genes encoding proteins, which undergo splice variation and post-translational processing, and may exist in monomeric or polymeric forms, producing a triple-stranded, twine-like structure. In man, principal family members include COL1A1 (COL1A1, P02452), COL2A1 (COL2A1, P02458), COL3A1 (COL3A1, P02461) and COL4A1 (COL4A1, P02462).

Receptors

DDR1 (discoidin domain receptor tyrosine kinase 1) Show summary » More detailed page

DDR2 (discoidin domain receptor tyrosine kinase 2) Show summary » More detailed page

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Type XVII RTKs: ROS receptors

Receptors

ROS (c-ros oncogene 1, receptor tyrosine kinase) Show summary » More detailed page

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Type XVIII RTKs: LMR family

Formerly known as: Lmr family

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The LMR kinases are unusual amongst the RTKs in possessing a short extracellular domain and extended intracellular domain (hence the ‘Lemur’ name reflecting the long tail). A precise function for these receptors has yet to be defined, although LMR1 was identified as a potential marker of apoptosis [15], giving rise to the name AATYK (Apoptosis-associated tyrosine kinase); while over-expression induces differentiation in neuroblastoma cells [40].

Receptors

Lmr1 (apoptosis-associated tyrosine kinase) Show summary » More detailed page

Lmr2 (lemur tyrosine kinase 2) Show summary » More detailed page

Lmr3 (lemur tyrosine kinase 3) Show summary » More detailed page

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Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family

Formerly known as: Leukocyte tyrosine kinase (LTK) receptor family

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The LTK family (ENSFM00500000270379) appear to lack endogenous ligands. LTK is subject to tissue-specific splice variation, which appears to generate products in distinct subcellular locations. ALK fusions created by gene translocations and rearrangements are associated with many types of cancer, including large cell lymphomas, inflammatory myofibrilastic tumours and non-small cell lung cancer [32].

Receptors

LTK (leukocyte receptor tyrosine kinase) Show summary » More detailed page

ALK (anaplastic lymphoma receptor tyrosine kinase) Show summary » More detailed page

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Type XX RTKs: STYK1

Formerly known as: TK-unique family

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Similar to the LMR RTK family, STYK1 has a truncated extracellular domain, but also displays a relatively short intracellular tail beyond the split kinase domain. STYK1 (also known as Novel Oncogene with Kinase-domain, NOK) has been suggested to co-localize with activated EGF receptor [12].

Receptors

STYK1 (serine/threonine/tyrosine kinase 1) Show summary » More detailed page

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