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Vol. 18, Issue 3, 732-742, March 2007

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Activated Cdc42-associated Kinase 1 Is a Component of EGF Receptor Signaling Complex and Regulates EGF Receptor Degradation

Feng Shen^*, Qiong Lin^*, Yan Gu, Chandra Childress^*, and Wannian Yang^*

*Weis Center for Research, Geisinger Clinic, Danville, PA 17822; and Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, PA 17033

Submitted February 16, 2006; Revised November 9, 2006; Accepted December 3, 2006
Monitoring Editor: Jean Gruenberg

Cdc42-associated tyrosine kinase 1 (ACK1) is a specific down-stream effector of Cdc42, a Rho family small G-protein. Previous studies have shown that ACK1 interacts with clathrin heavy chain and is involved in clathrin-coated vesicle endocytosis. Here we report that ACK1 interacted with epidermal growth factor receptor (EGFR) upon EGF stimulation via a region at carboxy terminus that is highly homologous to Gene-33/Mig-6/RALT. The interaction of ACK1 with EGFR was dependent on the kinase activity or tyrosine phosphorylation of EGFR. Immunofluorescent staining using anti-EGFR and GFP-ACK1 indicates that ACK1 was colocalized with EGFR on EEA-1 positive vesicles upon EGF stimulation. Suppression of the expression of ACK1 by ACK-RNAi inhibited ligand-induced degradation of EGFR upon EGF stimulation, suggesting that ACK1 plays an important role in regulation of EGFR degradation in cells. Furthermore, we identified ACK1 as an ubiquitin-binding protein. Through an ubiquitin-association (Uba) domain at the carboxy terminus, ACK1 binds to both poly- and mono-ubiquitin. Overexpression of the Uba domain-deletion mutant of ACK1 blocked the ligand-dependent degradation of EGFR, suggesting that ACK1 regulates EGFR degradation via its Uba domain. Taken together, our studies suggest that ACK1 senses signal of EGF and regulates ligand-induced degradation of EGFR.

Address correspondence to: Wannian Yang (wyang1{at}geisinger.edu)

Abbreviations used: ACK1, activated Cdc42-associated tyrosine kinase 1; EBD, EGFR-binding domain; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; RNAi, RNA interference; SHP-1, SH2-containing phosphatase-1.