The Cdc42 target ACK2 directly interacts with clathrin and influences clathrin assembly.
The Ras-related GTP-binding protein Cdc42 has been implicated in a diversity of biological functions including the regulation of intracellular trafficking and endocytosis. While screening for Cdc42 targets that influence these activities, we identified the protein-tyrosine kinase ACK2 (for activated Cdc42-associated kinase 2) as a new binding partner for clathrin. ACK2 binds clathrin via a domain that is conserved among a number of other clathrin-binding proteins including the arrestins and AP-2. Overexpression of ACK2 in NIH3T3 cells results in an inhibition of transferrin receptor endocytosis because of a competition between ACK2 and AP-2 for clathrin. Activated Cdc42 weakens the interaction between ACK2 and clathrin and thus reverses the ACK2-mediated inhibition of endocytosis. Overexpression of ACK2 increases the amount of clathrin present in fractions enriched in clathrin-coated vesicles. Taken together, our data suggest that ACK2 may represent a novel clathrin-assembly protein and participate in the regulation of receptor-mediated endocytosis.
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Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401, USA.
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D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D002966:Clathrin / Q000737:chemistry / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D016716:PC12 Cells; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011990:Receptors, Transferrin / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D018909:src Homology Domains
D002966:Clathrin; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D020764:cdc42 GTP-Binding Protein