drosophila activated cdc42 kinase has an anti-apoptotic function果蝇激活cdc42激酶具有抗凋亡作用.pdfVIP

Drosophila Activated Cdc42 Kinase Has an Anti-Apoptotic Function 1 1 1 2¤ Jessica A. Schoenherr , J. Michelle Drennan , Juan S. Martinez , Madhusudana Rao Chikka , 1 2 1 Mark C. Hall , Henry C. Chang , James C. Clemens * 1 Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America, 2 Department of Biology, Purdue University, West Lafayette, Indiana, United States of America Abstract Activated Cdc42 kinases (Acks) are evolutionarily conserved non-receptor tyrosine kinases. Activating somatic mutations and increased ACK1 protein levels have been found in many types of human cancers and correlate with a poor prognosis. ACK1 is activated by epidermal growth factor (EGF) receptor signaling and functions to regulate EGF receptor turnover. ACK1 has additionally been found to propagate downstream signals through the phosphorylation of cancer relevant substrates. Using Drosophila as a model organism, we have determined that Drosophila Ack possesses potent anti-apoptotic activity that is dependent on Ack kinase activity and is further activated by EGF receptor/Ras signaling. Ack anti-apoptotic signaling does not function through enhancement of EGF stimulated MAP kinase signaling, suggesting that it must function through phosphorylation of some unknown effector. We isolated several putative Drosophila Ack interacting proteins, many being orthologs of previously identified human ACK1 interacting proteins. Two of these interacting proteins, Drk and yorkie, were found to influence Ack signaling. Drk is the Drosophila homolog of GRB2, which is required to couple ACK1 binding t