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Molecular mechanism of the C-terminal Src kinase, Csk, and its role in oncogenesis

Lilly Wong

Appointment Period: 2002-2004, Grant Years: [18,19]

Lilly WongProtein kinases play a key part in signal transduction. They are involved in metabolism, gene expression, cell growth and motility, and cell differentiation and division. Hundreds of protein kinases have been identified, however much remains to be discovered in terms of regulation and activity. The Src-family tyrosine kinases, which are non-receptor kinases, are of special interest because their mechanism of regulation involves two noncatalytic domains, flanking the kinase domain. Catalytic activity of the cellular form of Src, c-Src, is regulated by an autoinhibitory mechanism that involves tight interaction of the phosphorylated C-terminus with the SH2 domain. A viral form of Src, v-Src, is a powerful cell transforming protein and is responsible for the transforming activity of Rous sarcoma virus. If catalytic activity is not regulated, many members of this family can potentially become oncogenic and life threatening. One major factor in regulation of Src-family members is phosphorylation of a tyrosine residue at the C-terminus. Csk regulates Src activity by phosphorylating the C-terminal tail. My thesis research examined the factors that control cell growth and differentiation through nonreceptor protein tyrosine kinase [nrPTKs]. Specifically, we are investigating the molecular mechanism whereby Csk negatively regulates Src and its family members.

Hamuro Y, Wong L, Shaffer J, Kim JS, Stranz DD, Jennings PA, Woods VL Jr, Adams JA. Phosphorylation driven motions in the COOH-terminal Src kinase, CSK, revealed through enhanced hydrogen-deuterium exchange and mass spectrometry (DXMS). J Mol Biol. (2002) 323:871-81. PMID: 12417200.

Rodriguez JC, Wong L, Jennings PA. The solvent in CNBr cleavage reactions determines the fragmentation efficiency of ketosteroid isomerase fusion proteins used in the production of recombinant peptides. Protein Expr Purif. (2003) 28:224-31. PMID: 12699685.

Wong L, Lieser S, Chie-Leon B, Miyashita O, Aubol B, Shaffer J, Onuchic JN, Jennings PA, Woods VL Jr, Adams JA. Dynamic coupling between the SH2 domain and active site of the COOH terminal Src kinase, Csk. J Mol Biol. (2004) 341:93-106. PMID: 15312765.

Wong L, Jennings PA, Adams JA. Communication pathways between the nucleotide pocket and distal regulatory sites in protein kinases. Acc Chem Res. (2004) 37:304-11. PMID: 15147171.

Lieser SA, Aubol BE, Wong L, Jennings PA, Adams JA. Coupling phosphoryl transfer and substrate interactions in protein kinases. Biochim Biophys Acta (2005) 1754:191-9. PMID: 16213199.

Wong L, Lieser SA, Miyashita O, Miller M, Tasken K, Onuchic JN, Adams JA, Woods VL Jr, Jennings PA. Coupled motions in the SH2 and kinase domains of Csk control Src phosphorylation. J Mol Biol. (2005) 351:131-43. PMID: 16002086.