| receptor protein-tyrosine kinase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 | |||||||||
| Identifiers | |||||||||
| EC no. | 2.7.10.1 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
| Identifiers | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Symbol | Pkinase_Tyr | ||||||||
| Pfam | PF07714 | ||||||||
| OPM superfamily | 186 | ||||||||
| OPM protein | 2k1k | ||||||||
| Membranome | 3 | ||||||||
| |||||||||
Receptor tyrosine kinases (RTKs) are the high-affinitycell surface receptors for many polypeptidegrowth factors,cytokines, andhormones. Of the 90 uniquetyrosine kinasegenes identified in thehuman genome, 58 encode receptor tyrosine kinase proteins.[1]Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types ofcancer.[2] Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression.[3] The receptors are generally activated by dimerization andsubstrate presentation. Receptor tyrosine kinases are part of the larger family ofprotein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as thenon-receptor tyrosine kinases which do not possess transmembrane domains.[4]
The first RTKs to be discovered were the EGF and NGF receptors in the 1960s, but the classification of receptor tyrosine kinases was not developed until the 1970s.[5]
Approximately 20 different RTK classes have been identified.[6]
Most RTKs are single subunit receptors but some exist asmultimeric complexes, e.g., theinsulin receptor that forms disulfide linked dimers in the presence of hormone (insulin); moreover, ligand binding to the extracellular domain induces formation of receptor dimers.[7] Eachmonomer has a single hydrophobictransmembrane-spanningdomain composed of 25 to 38amino acids, anextracellularN terminal region, and anintracellularC terminal region.[8] The extracellular N terminal region exhibits a variety of conserved elements including immunoglobulin (Ig)-like or epidermal growth factor (EGF)-like domains, fibronectin type III repeats, or cysteine-rich regions that are characteristic for each subfamily of RTKs; these domains contain primarily a ligand-binding site, which binds extracellularligands, e.g., a particulargrowth factor orhormone.[2] The intracellular C terminal region displays the highest level of conservation and comprises catalytic domains responsible for thekinase activity of these receptors, which catalyses receptor autophosphorylation and tyrosine phosphorylation of RTK substrates.[2]
Akinase is a type ofenzyme that transfersphosphate groups (see below) fromhigh-energy donor molecules, such asATP (see below) to specific target molecules (substrates); the process is termedphosphorylation. The opposite, an enzyme that removes phosphate groups from targets, is known as aphosphatase. Kinase enzymes that specifically phosphorylate tyrosine amino acids are termedtyrosine kinases.
When a growth factor binds to the extracellular domain of a RTK, itsdimerization is triggered with other adjacent RTKs.Dimerization leads to a rapid activation of the protein's cytoplasmic kinase domains, the first substrate for these domains being the receptor itself. The activated receptor as a result then becomes autophosphorylated on multiple specific intracellulartyrosineresidues.
Through diverse means, extracellular ligand binding will typically cause or stabilize receptor dimerization. This allows atyrosine in the cytoplasmic portion of each receptor monomer to betrans-phosphorylated by its partner receptor, propagating a signal through the plasma membrane.[9] The phosphorylation of specific tyrosine residues within the activated receptor creates binding sites forSrc homology 2 (SH2) domain- andphosphotyrosine binding (PTB) domain-containing proteins.[10][11]Specific proteins containing these domains includeSrc andphospholipase Cγ. Phosphorylation and activation of these two proteins on receptor binding lead to the initiation ofsignal transduction pathways. Other proteins that interact with the activated receptor act asadaptor proteins and have no intrinsic enzymatic activity of their own. These adaptor proteins link RTK activation to downstreamsignal transduction pathways, such as theMAP kinase signalling cascade.[2] An example of a vital signal transduction pathway involves the tyrosine kinase receptor, c-met, which is required for the survival and proliferation of migrating myoblasts duringmyogenesis. A lack of c-met disrupts secondary myogenesis and—as in LBX1—prevents the formation of limb musculature. This local action of FGFs (Fibroblast Growth Factors) with their RTK receptors is classified asparacrine signalling. As RTK receptors phosphorylate multipletyrosine residues, they can activate multiplesignal transduction pathways.
The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development ofneurodegenerative diseases, such asmultiple sclerosis andAlzheimer's disease.[12]In mice, loss of signaling by any member of the ErbB family results inembryonic lethality with defects in organs including thelungs,skin,heart, andbrain. Excessive ErbB signaling is associated with the development of a wide variety of types of solidtumor. ErbB-1 and ErbB-2 are found in many humancancers and their excessive signaling may be critical factors in the development andmalignancy of thesetumors.[13]
Fibroblast growth factors comprise the largest family of growth factor ligands at 23 members.[14] The naturalalternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 differentisoforms of FGFR.[15]These isoforms vary in their ligand binding properties and kinase domains; however, all share a common extracellular region composed of threeimmunoglobulin (Ig)-like domains (D1-D3), and thus belong to theimmunoglobulin superfamily.[16]Interactions with FGFs occur via FGFR domains D2 and D3. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor. This is not the case with FGF-7, however, which can activate only FGFR2b.[15] A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic tyrosine kinase domain, and one isoform, FGFR5γ, only contains the extracellular domains D1 and D2.[17]
Vascular endothelial growth factor (VEGF) is one of the main inducers ofendothelial cell proliferation and permeability ofblood vessels. Two RTKs bind to VEGF at the cell surface, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).[18]
The VEGF receptors have an extracellular portion consisting of sevenIg-like domains so, like FGFRs, belong to the immunoglobulin superfamily. They also possess a single transmembrane spanning region and an intracellular portion containing a splittyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). A third receptor has been discovered (VEGFR-3); however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediateslymphangiogenesis in response to VEGF-C and VEGF-D.
The naturalalternate splicing of theRETgene results in the production of 3 differentisoforms of the protein RET. RET51, RET43, and RET9 contain 51, 43, and 9amino acids in theirC-terminal tail, respectively.[19] The biological roles ofisoforms RET51 and RET9 are the most well studiedin vivo, as these are the most common isoforms in which RET occurs.
RET is the receptor for members of theglial cell line-derived neurotrophic factor (GDNF) family of extracellularsignalling molecules orligands (GFLs).[20]
In order to activate RET, first GFLs must form acomplex with aglycosylphosphatidylinositol (GPI)-anchoredco-receptor. The co-receptors themselves are classified as members of the GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (GFRα1-GFRα4) exhibit a specific binding activity for a specific GFLs.[21]Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggeringtrans-autophosphorylation of specifictyrosine residues within thetyrosine kinase domain of each RET molecule.Phosphorylation of thesetyrosines then initiates intracellularsignal transduction processes.[22]
Ephrin receptors are the largest subfamily of RTKs.
The DDRs are unique RTKs in that they bind tocollagens rather than soluble growth factors.[23]
The receptor tyrosine kinase (RTK) pathway is carefully regulated by a variety of positive andnegative feedback loops.[24] Because RTKs coordinate a wide variety of cellular functions such as cell proliferation and differentiation, they must be regulated to prevent severe abnormalities in cellular functioning such as cancer and fibrosis.[25]
Protein Tyrosine Phosphatase (PTPs) are a group of enzymes that possess a catalytic domain with phosphotyrosine-specific phosphohydrolase activity. PTPs are capable of modifying the activity of receptor tyrosine kinases in both a positive and negative manner.[26] PTPs can dephosphorylate the activated phosphorylated tyrosine residues on the RTKs[27] which virtually leads to termination of the signal. Studies involving PTP1B, a widely known PTP involved in the regulation of the cell cycle and cytokine receptor signaling, has shown to dephosphorylate the epidermal growth factor receptor[28] and the insulin receptor.[29] Some PTPs, on the other hand, are cell surface receptors that play a positive role in cell signaling proliferation. Cd45, a cell surface glycoprotein, plays a critical role in antigen-stimulated dephosphorylation of specific phosphotyrosines that inhibit the Src pathway.[30]
Herstatin is an autoinhibitor of the ErbB family,[31] which binds to RTKs and blocks receptor dimerization and tyrosine phosphorylation.[27] CHO cells transfected with herstatin resulted in reduced receptor oligomerization, clonal growth and receptor tyrosine phosphorylation in response to EGF.[32]
Activated RTKs can undergo endocytosis resulting in down regulation of the receptor and eventually the signaling cascade.[3] The molecular mechanism involves the engulfing of the RTK by a clathrin-mediated endocytosis, leading to intracellular degradation.[3]
RTKs have become an attractive target for drug therapy due to their implication in a variety of cellular abnormalities such as cancer, degenerative diseases and cardiovascular diseases. The United States Food and Drug Administration (FDA) has approved several anti-cancer drugs caused by activated RTKs. Drugs have been developed to target the extracellular domain or the catalytic domain, thus inhibiting ligand binding, receptor oligomerization.[33] Herceptin, a monoclonal antibody that is capable of binding to the extracellular domain of RTKs, has been used to treat HER2 overexpression in breast cancer.[34]
| Small Molecule | Target | Disease | Approval Year |
|---|---|---|---|
| Imatinib (Gleevec) | PDGFR, KIT, Abl, Arg | CML, GIST | 2001 |
| Gefitinib (Iressa) | EGFR | Esophageal cancer, Glioma | 2003 |
| Erlotinib (Tarceva) | EGFR | Esophageal cancer, Glioma | 2004 |
| Sorafenib (Nexavar) | Raf, VEGFR, PDGFR, Flt3, KIT | Renal cell carcinoma | 2005 |
| Sunitinib (Sutent) | KIT, VEGFR, PDGFR, Flt3 | Renal cell carcinoma, GIST, Endocrine pancreatic cancer | 2006 |
| Dasatinib (Sprycel) | Abl, Arg, KIT, PDGFR, Src | Imatinib-resistant CML | 2007 |
| Nilotinib (Tasigna) | Abl, Arg, KIT, PDGFR | Imatinib-resistant CML | 2007 |
| Lapatinib (Tykerb) | EGFR, ErbB2 | Mammary carcinoma | 2007 |
| Trastuzumab (Herceptin) | ErbB2 | Mammary carcinoma | 1998 |
| Cetuximab (Erbitux) | EGFR | Colorectal cancer, Head and neck cancer | 2004 |
| Bevacizumab (Avastin) | VEGF | Lung cancer, Colorectal cancer | 2004 |
| Panitumumab (Vectibix) | EGFR | Colorectal cancer | 2006 |
+ Table adapted from "Cell signalling by receptor-tyrosine kinases," by Lemmon and Schlessinger's, 2010.Cell,141, p. 1117–1134.
