Abstract
The C-terminal binding protein 1 (CtBP) is a ubiquitous corepressor linking the recruitment of DNA- and histone-modifying proteins to sequence-specific DNA-binding proteins and facilitating gene regulation during development and oncogenesis. We describe here the binding, phosphorylation and functional regulation of CtBP by the p21-activated kinase 1 (Pak1). Pak1 phosphorylates CtBP selectively on Ser158 within a putative regulatory loop, triggering CtBP cellular redistribution and blocking CtBP corepressor functions. A S158A substitution in CtBP or Pak1 knockdown by short interference RNA blocked CtBP phosphorylation, redistribution and attenuation of CtBP corepressor functions in reporter and chromatin assays. In the presence of NADH, Pak1 superphosphorylates CtBP and inhibits CtBP dehydrogenase activity, suggesting that preferential phosphorylation of active CtBP may alter secondary structures and influence both enzymatic and corepressor functions. Pak1 regulation of CtBP represents a new model of corepressor regulation whereby cellular signaling cascades may influence gene expression in mammalian cells.
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Acknowledgements
The authors thank G. Chinnadurai for providing a CtBP antibody, J. Chernoff for the Pak1 constructs, K. Georgopoulos for the Flag-CtBP constructs and critical reading of this manuscript, E. Fearon for the pGL2-E-cadherin promoter luciferase reporter, A. Hall for the V12 CDC42 construct, V. Kumar and A. Aggarwal for helpful discussion, and M.-C. Hung for the E1A vector. This work was supported by the US National Institutes of Health grants (R.K.) and in part by an M.D. Anderson Cancer Center Institutional Research Award (C.J.B.).
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Barnes, C., Vadlamudi, R., Mishra, S. et al. Functional inactivation of a transcriptional corepressor by a signaling kinase. Nat Struct Mol Biol 10, 622–628 (2003). https://doi.org/10.1038/nsb957
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DOI: https://doi.org/10.1038/nsb957
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