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Shen, F, Lin, Q, Gu, Y, Childress, C and Yang, W (2007) Activated Cdc42-associated kinase 1 is a component of EGF receptor signaling complex and regulates EGF receptor degradation. Mol. Biol. Cell 18:732-42
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.
Amino Acid Sequence; Animals; CHO Cells; COS Cells; Cercopithecus aethiops; Conserved Sequence; Cricetinae; Cricetulus; Epidermal Growth Factor/pharmacology; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins/chemistry; Intracellular Signaling Peptides and Proteins/metabolism; Mice; Molecular Sequence Data; Protein Binding/drug effects; Protein Processing, Post-Translational/drug effects; Protein Structure, Tertiary/drug effects; Protein-Tyrosine Kinases/chemistry; Protein-Tyrosine Kinases/metabolism; Receptor, Epidermal Growth Factor/metabolism; Signal Transduction/drug effects; Ubiquitin/metabolism