Growth factor receptors autophosphorylation

Igarashi, Y., Kitamura, K., Zhou, Q., and Hakomori, S., 1990, A role of lyso-phosphatidylcholine in GM3-dependent inhibition of epidermal growth factor receptor autophosphorylation in A431 plasma membranes, Biochem. Biophys. Res. Commun. 172 77-84. 

PETERSON G and BARNES s (1993) Genistein and hiochanin A inhibit the growth of hiunan prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate. 22 (4) 335-45. 

All RTKs contain between one and three tyrosines in the kinase activation loop, which is composed of subdomains VII and VIII of the protein kinase catalytic core. Phosphorylation of these tyrosines has been shown to be critical for stimulation of catalytic activity and biological function for a number of RTKs, including insulin receptor, FGF receptor, VEGF receptor, PDGF receptor, Met (hepatocyte growth factor receptor), and TrkA (NGF receptor). A major exception is the EGF receptor, for which autophosphorylation of a conserved tyrosine in the activation loop does not seem to be involved in signaling. Substitution of tyrosine with phenylalanine has no effect on RTK activity or downstream signals. 

In comparison to the level of cellular serine or threonine phosphorylation, protein tyrosine phosphorylation occurs at quite low levels in normal cells but dramatically increases upon oncogenic transformation or stimulation. Since the first discovery in 1978 that the transforming protein from Rous sarcoma virus (pp60vsrc) exhibited intrinsic kinase activity/5 protein kinase activity has also been shown to be inherent to other growth factor receptors such as epidermal growth factor receptor and the insulin receptor,[6 91 and to involve autophosphorylation processes. The diverse biochemical activity exhibited by protein tyrosine phosphorylation has stimulated the development of chemical methods for the preparation of phosphorylated peptides for use as substrates in elucidating the biochemical and physiological activity of phosphorylated site(s). 

Enzyme receptors are transmembrane receptors with intrinsic enzymatic activity. Examples are the receptor tyrosine kinases (RTKs), which autophosphorylate their own tyrosine residues, such as the growth factor receptors and the insulin receptor. And, finally, there are the intracellular DNA sinding receptors. They bind lipophilic ligands that pass through the membrane. They address genes directly. Examples are the steroid hormone receptors (see Chapter 11). (This figure was donated by Professor Martin Lohse, University of Wurzburg.)... 

Lopez-Ilasaca, M., Schiene, C., Kullertz, G., Tradler, T., Fischer, G., and Wetzker, R. (1998). Effects of FK506-binding protein 12 and FK506 on autophosphorylation of epidermal growth factor receptor. J. Biol. Chem. 273, 9430-9434. 

Ras is known to be involved in the regulation of cellular proliferation and terminal differentiation [7,40]. In mammals, ras is activated by growth-factor-receptor tyrosine kinases and other tyrosine kinases. Some of these kinases phosphorylate the She protein and phosphorylated She plus autophosphorylated receptor proteins bind the SH2 domain... 

Ferracini, R. Longati, R Naldini, L. Vigna, E. Comoglio, P.M. Identification of the major autophosphorylation site of the Met/hepatocyte growth factor receptor tyrosine kinase. J. Biol. Chem., 266, 19558-19564 (1991)... 

Typically, the activated protein tyrosine kinases of growth factor receptors catalyze the autophosphorylation of a number of tyrosine residues on the cytoplasmic domains of the adjacent receptor molecule. These phosphorylated residues provide docking sites for both effector and adaptor proteins that mediate downstream signaling pathways. 

Structural studies of some growth factor receptor protein tyrosine kinases have shown that the autophosphorylation occurs at tyrosine residues in an activation loop of the polypeptide chain. When this loop is not phosphorylated, it restricts access of ATP to the active site of the kinase. Upon phosphorylation it moves, so as to allow ATP ready access to the site, leading to the generation of a high-activity form of the enzyme. 

Downward, J., Parker, P., and Waterfield, M.D., Autophosphorylation sites on the epidermal growth factor receptor, iVafure, 311,483, 1984. 

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