Receptor tyrosine kinases biological roles

Protein tyrosine phosphatases play a crucial role in the control of the activity of receptor tyrosine kinases, nonreceptor tyrosine kinases, and the signaling pathways that they regulate. The importance of the tyrosine phosphatases for receptor tyrosine kinase signaling is illustrated by the observation that virtually all receptor tyrosine kinases can be activated, even in the absence of ligand, by treatment of cells with tyrosine phosphatase inhibitors, demonstrating that the activity of tyrosine kinases is continuously controlled by inhibitory tyrosine phosphatase action. As outlined above, the activity of most receptor tyrosine kinases is positively controlled by Tyr-phosphorylation in the activation loop. Protein tyrosine phosphatases that remove these stimulatory phosphate residues will inhibit receptor activity and the biological responses mediated by Tyr-phosphorylation-dependent signaling pathways. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

There is recent data to suggest that there may in fact be a biological role for the internalized insulin and EGF receptors (both of which are themselves tyrosine kinases). Thus, microinjection of insulin-occupied insulin receptors into Xenopus oocytes causes the increased phosphorylation of ribosomal protein S6 (a known substrate for the insulin receptor/kinase) [62] and the EGF receptor in endocytic vesicles has been shown to retain its kinase activity [63]. Whether the internalized insulin receptor/kinase or EGF receptor/kinase has a physiological role or not is as yet unknown. Clearly, though, these data suggest that there is much more to be learned about the role of internalized hormone-receptor complexes, especially those where the receptor possesses intrinsic enzymatic activity. 

Kato, H., Faria, T.N., Stannard, B., Roberts, C.T., and Leroiths, D. 1993. Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the. Journal of Biological, 4, 2655-2661. 

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