Aberrant activation of
tyrosine kinases is linked causally to human
cancers. Activated Cdc42-associated
kinase (Ack1), an intracellular
tyrosine kinase, has primarily been studied for its signaling properties but has not been linked to specific pathologic conditions. Herein, we report that expression of activated Ack1 in LNCaP cells, while minimally increasing growth in culture, enhanced anchorage-independent growth in vitro and dramatically accelerated
tumorigenesis in nude mice.
Molecular chaperone heat shock protein 90beta (Hsp90beta)-bound Ack1 and treatment of cells with
geldanamycin, a Hsp90 inhibitor, inhibited Ack1
kinase activity and suppressed
tumorigenesis. Further, we identify the
tumor suppressor
WW domain containing oxidoreductase (Wwox) as an Ack1-interacting
protein. Activated Ack1
tyrosine phosphorylated Wwox, leading to rapid dissociation of the Ack1-Wwox complex and concomitant Wwox polyubiquitination followed by degradation.
Tyrosine phosphorylation of Wwox was critical for its degradation, as splice variant WwoxDelta5-8 that was not phosphorylated by Ack1 failed to undergo polyubiquitination and degradation. It has been reported that phosphorylation of Wwox at Tyr33 stimulated its proapoptotic activity. We observed that Y33F Wwox mutant was still
tyrosine phosphorylated and polyubiquitinated by Ack1 action. Site-directed mutagenesis revealed that activated Ack1 primarily phosphorylated Wwox at Tyr287, suggesting that phosphorylation of distinct
tyrosine residues activate or degrade Wwox. Primary
androgen-independent prostate
tumors but not benign prostate showed increased
tyrosine-phosphorylated Ack1 and decreased Wwox. Taken together, these data indicate that Ack1 stimulated prostate
tumorigenesis in part by negatively regulating the proapoptotic
tumor suppressor, Wwox. Further, these findings suggest that Ack1 could be a novel therapeutic target for
prostate cancer.