p21-activated protein kinase γ-PAK is activated by ionizing radiation and other DNA-damaging agents. Similarities and differences to α-PAK

Abstract

The p21-activated protein kinase γ-PAK is activated 2-5-fold in response to ionizing radiation (IR) in 3T3-L1 fibroblasts and U937 leukemia cells, γ-PAK is activated in a dose- and time-dependent manner. Doses from 1 to 100 Gy result in significant stimulation of activity at 30 min, whereas maximal stimulation is observed at 120 min after irradiation. UV (80 J/m2) and the DNA-damaging drugs cytosine β-o-arabinofuranoside (AraC) and cis- platinum(II)diammine dichloride (cisplatin) also induce γ-PAK activation. The activation of γ-PAK in response to IR or AraC is dependent on tyrosine kinase and phosphoinositide 3-kinase activity, as demonstrated by use of the inhibitors genistein and wortmannin; in contrast activation of γ-PAK by cisplatin and UV is not affected significantly by these inhibitors, suggesting that γ-PAK can be activated by more than one pathway in response to different types of DNA damage. In contrast to γ-PAK, α-PAK and JNK are activated only by cisplatin and UV in 3T3-L1 cells, suggesting differential regulation of the protein kinases. This is the first time that members of the Ste20/PAK family of protein kinases have been shown to be involved in the cellular response to IR and other DNA-damaging agents.