Activated Cdc42-associated kinase 1 is a component of EGF receptor signaling complex and regulates EGF receptor degradation.
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.
Mesh Terms:
Amino Acid Sequence, Animals, CHO Cells, COS Cells, Cercopithecus aethiops, Conserved Sequence, Cricetinae, Cricetulus, Epidermal Growth Factor, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Signal Transduction, Ubiquitin
Amino Acid Sequence, Animals, CHO Cells, COS Cells, Cercopithecus aethiops, Conserved Sequence, Cricetinae, Cricetulus, Epidermal Growth Factor, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Signal Transduction, Ubiquitin
Mol. Biol. Cell
Date: Mar. 01, 2007
PubMed ID: 17182860
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