Journal
GROWTH FACTORS
Volume 28, Issue 5, Pages 329-350Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/08977194.2010.484424
Keywords
Protein kinase; Src-family kinases; CSK; CHK; allosteric regulation; catalysis
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Funding
- National Health and Medical Research Council of Australia
- Cancer Council Victoria
- Australian Institute of Nuclear Science and Engineering
- Dowd Neuroscience Postgraduate Research Fellowship
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C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are endogenous inhibitors constraining the activity of the oncogenic Src-family kinases (SFKs) in cells. Both kinases suppress SFKs by selectively phosphorylating their consensus C-terminal regulatory tyrosine. In addition to phosphorylation, CHK can suppress SFKs by a unique non-catalytic inhibitory mechanism that involves tight binding of CHK to SFKs to form stable complexes. In this review, we discuss how allosteric regulators, phosphorylation, and inter-domain interactions interplay to govern the activity of CSK and CHK and their ability to inhibit SFKs. In particular, based upon the published results of structural and biochemical analysis of CSK and CHK, we attempt to chart the allosteric networks in CSK and CHK that govern their catalysis and ability to inhibit SFKs. We also discuss how the published three-dimensional structure of CSK complexed with an SFK member sheds light on the structural basis of substrate recognition by protein kinases.
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