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MBC in Press, published online ahead of print December 20, 2006
Mol. Biol. Cell 10.1091/mbc.E06-02-0142

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Submitted on February 16, 2006
Revised on November 9, 2006
Accepted on December 3, 2006

Activated Cdc42-associated Kinase 1 (ACK1) Is a Component of EGF Receptor Signaling Complex and Regulates EGF Receptor Degradation

Feng Shen,* Qiong Lin,* Yan Gu,{dagger} Chandra Childress,* and Wannian Yang*

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

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)




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C. Huber, A. Martensson, G. M. Bokoch, D. Nemazee, and A. L. Gavin
FGD2, a CDC42-specific Exchange Factor Expressed by Antigen-presenting Cells, Localizes to Early Endosomes and Active Membrane Ruffles
J. Biol. Chem., December 5, 2008; 283(49): 34002 - 34012.
[Abstract] [Full Text] [PDF]


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