Autoregulatory Mechanisms in Protein-tyrosine Kinases

Abstract

Protein-tyrosine kinases (PTKs), 1The abbreviations used are: PTK, protein-tyrosine kinase; RTK, receptor tyrosine kinase; NRTK, non-receptor tyrosine kinase; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; SH2, Src homology 2; PTB, phosphotyrosine-binding; pTyr, phosphorylated Tyr; IRS-1, insulin receptor substrate 1; IRK, insulin receptor kinase domain; FGFR1K, FGF receptor 1 kinase domain; IRK0P, unphosphorylated IRK; IRK3P, tris-phosphorylated IRK; AMP-PNP, adenosine 5′-(β,γ-imino)triphosphate.1The abbreviations used are: PTK, protein-tyrosine kinase; RTK, receptor tyrosine kinase; NRTK, non-receptor tyrosine kinase; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; SH2, Src homology 2; PTB, phosphotyrosine-binding; pTyr, phosphorylated Tyr; IRS-1, insulin receptor substrate 1; IRK, insulin receptor kinase domain; FGFR1K, FGF receptor 1 kinase domain; IRK0P, unphosphorylated IRK; IRK3P, tris-phosphorylated IRK; AMP-PNP, adenosine 5′-(β,γ-imino)triphosphate. enzymes that catalyze the transfer of the γ-phosphate of ATP to tyrosine residues of protein substrates, are critical components of signaling pathways that control cellular proliferation and differentiation. PTKs can be subdivided into two large families, receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs) (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar, 2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar). RTKs span the plasma membrane and contain an extracellular portion, which binds ligand, and an intracellular portion, which possesses catalytic activity and regulatory sequences. The RTK family includes the insulin receptor and the receptors for many growth factors such as epidermal (EGF), platelet-derived (PDGF), fibroblast (FGF), and nerve growth factors (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar). NRTKs contain no extracellular or transmembrane portion but possess modular domains that are responsible for subcellular targeting and regulation of catalytic activity. The NRTK family includes Src, Abl, FAK, and the JAKs among many others (2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar). Because of the key roles PTKs play in cellular signaling processes, their catalytic activity is tightly controlled in normal cells by protein-tyrosine phosphatases, by other protein tyrosine or serine/threonine kinases (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar), and by autoregulatory mechanisms. The recent crystallographic structures of several members of both the RTK and NRTK families, together with extensive biochemical studies, afford an understanding at the molecular level of the autoregulation mechanisms to which PTKs are subject.Receptor Tyrosine KinasesThe RTK family can be broadly divided into two groups depending on the covalent organization of the receptor. Most RTKs possess a single polypeptide chain and are monomeric in the absence of ligand. Members of the insulin receptor subfamily, which includes insulin-like growth factor-1 receptor, are disulfide-linked dimers of two polypeptide chains, forming an α2β2 heterotetramer. Ligand binding to the extracellular portion of RTKs leads to dimerization of monomeric receptors or a rearrangement within the quaternary structure of heterotetrameric receptors, resulting in autophosphorylation of specific tyrosine residues in the cytoplasmic portion (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar).In general, tyrosine autophosphorylation either stimulates the intrinsic catalytic (kinase) activity of the receptor or generates recruitment sites for downstream signaling proteins containing phosphotyrosine-recognition domains, such as the Src homology 2 (SH2) domain or the phosphotyrosine-binding (PTB) domain (3Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). The vast majority of PTKs contain between one and in the kinase which and of the protein kinase catalytic T. Scopus Google Scholar). of to be critical for of catalytic activity and for RTKs such as the insulin receptor Cell. Full Text PDF PubMed Scopus Google Scholar), FGF receptor A. Schlessinger J. Cell. PubMed Scopus Google Scholar), growth receptor A. Google Scholar), and nerve growth receptor G. Google Scholar), and for NRTKs such as Src Cell. Full Text PDF PubMed Scopus Google Scholar), T. T. J. 1995; PubMed Scopus Google Scholar), and J. T. Cell. 17: PubMed Scopus Google of protein by RTKs of receptor catalytic activity but of protein to the receptor a a autophosphorylation of in FGF receptor 1 a binding for the domain of The of the do