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Clin Exp Pharmacol Physiol. 2010 Jan;37(1):93-101. doi: 10.1111/j.1440-1681.2009.05237.x. Epub 2009 Jun 29.

Allosteric networks governing regulation and catalysis of Src-family protein tyrosine kinases: implications for disease-associated kinases.

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  • 1Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia. heung@unimelb.edu.au

Abstract

1. The Src-family protein tyrosine kinases (SFKs) are multidomain oncogenic protein tyrosine kinases. Their overactivation contributes to cancer formation and progression. Thus, synthetic inhibitors of SFKs are being developed as therapeutics for cancer treatment. Understanding the regulatory and catalytic mechanisms of SFKs is necessary for the development of therapeutic SFK inhibitors. 2. Although many upstream regulators and protein substrates of SFKs have been identified, both the mechanisms of activation and catalysis of SFKs are not fully understood. In particular, it is still unclear how the inactive SFKs undergo conformational transition during activation. The mechanism governing the binding of substrates and the release of products during catalysis is another area that requires investigation. 3. Several recent publications indicate the presence of a 'hydrophobic spine' formed by four conserved interacting hydrophobic residues in the kinase domain of SFKs. In the present review, we discuss how the assembly and disassembly of the hydrophobic spine residues may govern conformational transition of SFKs during activation. In addition to regulation of kinase activity, the hydrophobic spine is implicated to be involved in catalysis. It has been postulated recently that perturbation of the hydrophobic spine residues is a key step in catalysis. 4. Further investigations to decipher the roles of the hydrophobic spine residues in regulation and catalysis of SFKs will benefit the development of therapeutic SFK inhibitors for cancer treatment.

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