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

Authors :
Frank DiPino
Amelia Poplawski
Jun Ling
Jolinda A. Traugh
John Huang
Allen Huang
Source :
Biochimica et biophysica acta. Molecular cell research. 1867(4)
Publication Year :
2019

Abstract

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.

Details

ISSN :
18792596
Volume :
1867
Issue :
4
Database :
OpenAIRE
Journal :
Biochimica et biophysica acta. Molecular cell research
Accession number :
edsair.doi.dedup.....dcf7c0307f232b52a9b3994301428f20