TI - Mechanism of p21-activated kinase 6-mediated inhibition of androgen receptor signaling . AB - PAK6 was first identified as an androgen receptor ( AR ) -interacting protein able to inhibit AR -mediated transcriptional responses . PAK6 is a serine/threonine kinase belonging to the p21-activated kinase ( PAK ) family implicated in actin reorganization and cell motility , gene transcription , apoptosis , and cell transformation . We investigated the biochemical basis for inhibition of AR signaling by PAK6 . We compared the kinase activity of PAK6 with two well characterized members of the PAK family , PAK1 and PAK4 . Like PAK4 , PAK6 possesses a constitutive basal kinase activity that , unlike PAK1 , is not modulated by the binding of active Rac or Cdc42 GTPases . In order to test the involvement of PAK6 kinase activity in suppression of AR -mediated transcription , we generated kinase -dead ( K436A ) and kinase -active ( S531N ) mutants of PAK6 . We show that PAK6 kinase activity is required for effective PAK6 -induced repression of AR signaling . Suppression does not depend upon GTPase binding to PAK6 and is not mimicked by the closely related PAK1 and PAK4 isoforms . Kinase -dependent inhibition by PAK6 extended to the enhanced AR -mediated transcription seen in the presence of coactivating molecules and to the action of AR coinhibitors . Active PAK6 inhibited nuclear translocation of the stimulated AR , suggesting a possible mechanism for inhibition of AR responsiveness . Finally , we observe that autophosphorylated , active PAK6 protein is differently expressed among prostate cancer cell lines . Modulation of PAK6 activity may be responsible for regulation of AR signaling in various forms of prostate cancer .