Pp Pp

Receptor Tyrosine Kinases Tyrosine Kinase

Associated Receptors

FIGURE 17 Prototypic tyrosine-kinase-dependent receptors. Receptor tyrosine kinases contain an intrinsic tyrosine kinase catalytic domain (indicated in blue) in the part of the receptor that extends into the cytosol. In the absence of ligand, they usually consist of a single peptide chain (1) which forms a dimer after binding to its agonist (A). Some receptor tyrosine kinases (2) are more complex, with subunits held together by disulfide bonds, whether or not the agonist is present. The tyrosine-kinase-associated receptors have no intrinsic catalytic activity but associate with cytosolic tyrosine kinases (indicated in blue). Some of these receptors (4) are composed of two or more dissimilar subunits in the absence of agonist, but all form dimers in the presence of agonist. Dimers of receptor tyrosine kinases contain two molecules of agonist, while dimers of the tyrosine-kinase-associated receptors contain only one molecule of agonist. Dimerization upon receptor binding leads to phosphorylation (P) on tyrosine residues in the receptor itself or perhaps on the associated kinase as well.

extracellular portions contain the ligand binding site. Agents that excite these receptors often promote cell division (mitogens) or differentiation. Their actions, which generally, but not exclusively, involve changes in gene expression, are slower in onset and more prolonged than most effects of ligands that act through G-protein-linked receptors. A notable exception is insulin (see Chapter 41), which may increase glucose transport across plasma membranes within just a few minutes.

For most of the tyrosine-kinase-dependent receptors, agonist binding causes two receptor molecules to come together to form a dimer as the first step in signal generation. Dimerization brings the cytosolic portions into close proximity to each other and permits the tyrosine kinase associated with each member of the dimer to phosphorylate tyrosine residues on the other. Dimerization generally produces a complex of two receptor tyrosine kinase molecules along with one or two agonist molecules. The insulin and insulin-like growth factor (IGF) receptors, which are dimeric even in the unliganded state (see Chapters 41 and 44), become activated upon binding two agonist molecules. The platelet-derived growth factor (PDGF) receptor complex is formed when a dimer PDGF binds to two receptor molecules. Tyrosine-kinase-associated receptors for growth hormone (see Chapter 44), prolactin (see Chapter 47), erythropoietin and many cytokines form dimers when two receptor molecules bind a single agonist molecule. Some of the tyrosine kinase-associated receptors have two or three subunits so that each half of the dimer contains an agonist binding subunit and a signaling subunit that binds to tyrosine kinase. Curiously, the same signaling subunit, called gp130, is found in receptors for several different cytokines.

The protein substrates for receptor-activated tyrosine kinases may have catalytic activity or may act only as scaffolds or adaptor proteins to which other proteins are recruited and positioned so that enzymatic modifications are facilitated. Phosphorylated tyrosines act as docking sites for proteins that contain so-called Src homology 2 (SH2) domains. SH2 domains are named for the particular configuration of the tyrosine phosphate binding region originally discovered in v-Src, the cancer-inducing protein tyrosine kinase of the Rous sarcoma virus. SH2 domains represent one type of a growing list of modules within proteins that recognize and bind to specific complementary motifs in other proteins. Different SH2 groups recognize phosphory-lated tyrosines in different contexts of adjacent amino acid residues. Typically, multiple tyrosines are phos-phorylated so that several different SH2-containing proteins are recruited and initiate multiple signaling pathways.

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