title: Drosophila activated Cdc42 kinase has an anti-apoptotic function.
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 to receptor tyrosine kinases. Drk knockdown blocks Ack survival activity, suggesting that Ack localization is important for its pro-survival activity. Yorkie is a transcriptional co-activator that is downstream of the Salvador-Hippo-Warts pathway and promotes transcription of proliferative and anti-apoptotic genes. We find that yorkie and Ack synergistically interact to produce tissue overgrowth and that yorkie loss of function interferes with Ack anti-apoptotic signaling. Our results demonstrate how increased Ack signaling could contribute to cancer when coupled to proliferative signals.
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Schoenherr
authors.forename: J Michelle
authors.initials: JM
authors.lastname: Drennan
authors.forename: Juan S
authors.initials: JS
authors.lastname: Martinez
authors.forename: Madhusudana Rao
authors.initials: MR
authors.lastname: Chikka
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hall
authors.forename: Henry C
authors.initials: HC
authors.lastname: Chang
authors.forename: James C
authors.initials: JC
authors.lastname: Clemens
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development; D066246:ErbB Receptors / Q000378:metabolism; D005123:Eye / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020935:MAP Kinase Signaling System / Q000235:genetics; D009154:Mutation; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: C090145:Cdc42 protein, Drosophila; D029721:Drosophila Proteins; C108880:HID protein, Drosophila; D009479:Neuropeptides; D009687:Nuclear Proteins; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C080530:drk protein, Drosophila; C498593:Ack protein, Drosophila; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins