Protein 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, that lacks. It is a powerful cell transforming protein and is responsible for the Rous sarcoma virus. If catalytic activity is not regulated, any member of this family can potentially become oncogenic and life threatening. In essence, regulation of catalytic activity is very important. 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. Thus, it is important that we understand how Csk functions. My thesis project focuses on understanding 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.

PUBLICATIONS (resulting from this training)

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

Rodriguez JC, Wong L, Jennings PA. (2003) 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. 28:224-31.

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

Boyd AE, Dunlop CS, Wong L, Radic Z, Taylor P, Johnson DA. (2004) Nanosecond dynamics of acetylcholinesterase near the active center gorge. J Biol Chem. 279:26612-8.

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

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

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