Receptor tyrosine kinase

Class of enzymes

Receptor tyrosine kinases (RTKs) are the high affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. 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 of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression.

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.

Most RTKs are single subunit receptors but some exist as multimeric complexes, e. g., the insulin receptor that forms disulfide linked dimers in the presence of hormone (insulin); moreover, ligand binding to the extracellular domain induces formation of receptor dimers. Each monomer has a single hydrophobic transmembrane spanning domain composed of 25 to 38 amino acids, an extracellular N terminal region, and an intracellular C terminal region. 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 extracellular ligands, e. g., a particular growth factor or hormone. The phosphorylation of specific tyrosine residues within the activated receptor creates binding sites for Src homology 2 (SH2) domain and phosphotyrosine binding (PTB) domain containing proteins. Specific proteins containing these domains include Src and phospholipase Cγ. Phosphorylation and activation of these two proteins on receptor binding lead to the initiation of signal transduction pathways. Other proteins that interact with the activated receptor act as adaptor proteins and have no intrinsic enzymatic activity of their own. These adaptor proteins link RTK activation to downstream signal transduction pathways, such as the MAP kinase signalling cascade. In mice, loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart, and brain. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB 1 and ErbB 2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors.

Fibroblast growth factors comprise the largest family of growth factor ligands at 23 members. The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR. These isoforms vary in their ligand binding properties and kinase domains; however, all share a common extracellular region composed of three immunoglobulin (Ig) like domains (D1 D3), and thus belong to the immunoglobulin superfamily. 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.

Vascular endothelial growth factor (VEGF) is one of the main inducers of endothelial cell proliferation and permeability of blood vessels. Two RTKs bind to VEGF at the cell surface, VEGFR 1 (Flt 1) and VEGFR 2 (KDR/Flk 1). The VEGF receptors have an extracellular portion consisting of seven Ig like domains so, like FGFRs, belong to the immunoglobulin superfamily. They also possess a single transmembrane spanning region and an intracellular portion containing a split tyrosine 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 mediates lymphangiogenesis in response to VEGF C and VEGF D.

The natural alternate splicing of the RET gene results in the production of 3 different isoforms of the protein RET. RET51, RET43, and RET9 contain 51, 43, and 9 amino acids in their C terminal tail, respectively. The biological roles of isoforms RET51 and RET9 are the most well studied in vivo, as these are the most common isoforms in which RET occurs. RET is the receptor for members of the glial cell line derived neurotrophic factor (GDNF) family of extracellular signalling molecules or ligands (GFLs). In order to activate RET, first GFLs must form a complex with a glycosylphosphatidylinositol (GPI) anchored co 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. Upon GFL GFRα complex formation, the complex then brings together two molecules of RET, triggering trans autophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each RET molecule. Phosphorylation of these tyrosines then initiates intracellular signal transduction processes.

Ephrin receptors are the largest subfamily of RTKs.

The DDRs are unique RTKs in that they bind to collagens rather than soluble growth factors.

The receptor tyrosine kinase (RTK) pathway is carefully regulated by a variety of positive and negative feedback loops. 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.

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. PTPs can dephosphorylate the activated phosphorylated tyrosine residues on the RTKs 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 and the insulin receptor. 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.

Herstatin is an autoinhibitor of the ErbB family, which binds to RTKs and blocks receptor dimerization and tyrosine phosphorylation.