PAK2 activated by Cdc42 and caspase 3 mediates different cellular responses to oxidative stress-induced apoptosis.

Autor: Huang J; Department of Biochemistry, University of California, Riverside, CA 92521, United States of America., Huang A; Canyon Crest Academy, San Diego, CA 92130, United States of America., Poplawski A; Geisinger Commonwealth School of Medicine, Scranton, PA 18509, United States of America; Misericordia University, Dallas, PA 18612, United States of America., DiPino F Jr; Misericordia University, Dallas, PA 18612, United States of America., Traugh JA; Department of Biochemistry, University of California, Riverside, CA 92521, United States of America., Ling J; California University of Science and Medicine, Colton, CA 92324, United States of America; Geisinger Commonwealth School of Medicine, Scranton, PA 18509, United States of America; Department of Biochemistry, University of California, Riverside, CA 92521, United States of America. Electronic address: lingj@cusm.org.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular cell research [Biochim Biophys Acta Mol Cell Res] 2020 Apr; Vol. 1867 (4), pp. 118645. Date of Electronic Publication: 2020 Jan 08.
DOI: 10.1016/j.bbamcr.2020.118645
Abstrakt: p21-activated protein kinase (PAK2) is a unique member of the PAK family kinases that plays important roles in stress signaling. It can be activated by binding to the small GTPase, Cdc42 and Rac1, or by caspase 3 cleavage. Cdc42-activated PAK2 mediates cytostasis, whereas caspase 3-cleaved PAK2 contributes to apoptosis. However, the relationship between these two states of PAK2 activation remains elusive. In this study, through protein biochemical analyses and various cell-based assays, we demonstrated that full-length PAK2 activated by Cdc42 was resistant to the cleavage by caspase 3 in vitro and within cells. When mammalian cells were treated by oxidative stress using hydrogen peroxide, PAK2 was highly activated through caspase 3 cleavage that led to apoptosis. However, when PAK2 was pre-activated by Cdc42 or by mild stress such as serum deprivation, it was no longer able to be cleaved by caspase 3 upon hydrogen peroxide treatment, and the subsequent apoptosis was also largely inhibited. Furthermore, cells expressing active mutants of full-length PAK2 became more resistant to hydrogen peroxide-induced apoptosis than inactive mutants. Taken together, this study identified two states of PAK2 activation, wherein Cdc42- and autophosphorylation-dependent activation inhibited the constitutive activation of PAK2 by caspase cleavage. The regulation between these two states of PAK2 activation provides a new molecular mechanism to support PAK2 as a molecular switch for controlling cytostasis and apoptosis in response to different types and levels of stress with broad physiological and pathological relevance.
Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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