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Autophosphorylation-dependent degradation of Pak1, triggered by the Rho-family GTPase, Chp

Weisz Hubsman, Monika, Volinsky, Natalia, Manser, Edward, Yablonski, Deborah, Aronheim, Ami·2007·Biochemical Journal
DOI 10.1042/bj20061696
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Abstract

The Paks (p21-activated kinases) Pak1, Pak2 and Pak3 are among the most studied effectors of the Rho-family GTPases, Rac, Cdc42 (cell division cycle 42) and Chp (Cdc42 homologous protein). Pak kinases influence a variety of cellular functions, but the process of Pak down-regulation, following activation, is poorly understood. In the present study, we describe for the first time a negative-inhibitory loop generated by the small Rho-GTPases Cdc42 and Chp, resulting in Pak1 inhibition. Upon overexpression of Chp, we unexpectedly observed a T-cell migration phenotype consistent with Paks inhibition. In line with this observation, overexpression of either Chp or Cdc42 caused a marked reduction in the level of Pak1 protein in a number of different cell lines. Chp-induced degradation was accompanied by ubiquitination of Pak1, and was dependent on the proteasome. The susceptibility of Pak1 to Chp-induced degradation depended on its p21-binding domain, kinase activity and a number of Pak1 autophosphorylation sites, whereas the PIX- (Pak-interacting exchange factor) and Nck-binding sites were not required. Together, these results implicate Chp-induced kinase autophosphorylation in the degradation of Pak1. The N-terminal domain of Chp was found to be required for Chp-induced degradation, although not for Pak1 activation, suggesting that Chp provides a second function, distinct from kinase activation, to trigger Pak degradation. Collectively, our results demonstrate a novel mechanism of signal termination mediated by the Rho-family GTPases Chp and Cdc42, which results in ubiquitin-mediated degradation of one of their direct effectors, Pak1.

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Metadata

Authors
Weisz Hubsman, M., Volinsky, N., Manser, E., Yablonski, D., & Aronheim, A.
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2007-05-29
Volume
404
Issue
3
Pages
487-497
ISSN
  • 0264-6021
  • 1470-8728
DOI
10.1042/bj20061696
Cited by
56
References
0
Language
en

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CoChat. (2026). Citation check: Autophosphorylation-dependent degradation of Pak1, triggered by the Rho-family GTPase, Chp. https://app.cochat.ai/papers/10.1042/bj20061696
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Weisz Hubsman, M., Volinsky, N., Manser, E., Yablonski, D., & Aronheim, A. (2007). Autophosphorylation-dependent degradation of Pak1, triggered by the Rho-family GTPase, Chp. Biochemical Journal. https://doi.org/10.1042/bj20061696