Biochemical and structural basis of the tumour suppression mechanism of CSK-homologous kinase
Src-family kinases (SFKs) are protein products of the Src-family of oncogenes and proto-oncogenes. Constitutive activation of SFKs contributes to many forms of cancer.
In normal cells, SFKs are kept in the inactive form by phosphorylation of the C-terminal regulatory tyrosyl residue (referred to as YT). CSK-homologous kinase (CHK) is a major endogenous inhibitor constraining SFK activities in cells.
Figure 1: CHK-optimal peptide, which contains the consensus phosphorylation sequence, is a specific and efficient in vitro substrate of CHK.
We and other researchers discovered that CHK inhibits SFKs by:
- phosphorylating YT of SFKs
- a novel non-catalytic mechanism which involves direct binding to SFKs to form a stable protein complex
In the latter mechanism, the binding alone is sufficient to suppress SFK activity. Since CHK constrains the oncogenic action of SFKs, it is a potential tumour suppressor in both solid tumours and leukaemia.
In addition to phosphorylating SFKs, CHK can phosphorylate other cellular proteins. Whether phosphorylation of the non-SFK substrate contributes to the tumour suppressor activity of CHK is currently under investigation.
Using peptide library screening, we and our collaborators have defined the optimal phosphorylation sequence for CHK (Figure 1). Our findings will facilitate the search for other cellular protein substrates of CHK and have allowed us to develop a convenient assay to monitor CHK activity in cells.
This project focuses on deciphering:
- the structural basis of two inhibitory mechanisms employed by CHK to constrain SFK activity
- how CHK activity and expression are regulated in cancer cells
- how expression of CHK induces apoptosis and growth arrest of the cancer cells.
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