Abstract
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.
Highlights
The interactions of Cdc42 with its various effector proteins give rise to actin cytoskeletal rearrangements that influence cell shape and motility, as well as stimulate cell-cycle progression and under some conditions, malignant transformation [1,2,3]
The ACKs (ACK1 and ACK2)1 are nonreceptor-tyrosine kinases that share some similarity with the focal adhesion kinase (FAK) and protein-tyrosine kinase 2 (PYK2) and serve as highly specific target/effectors for the Ras-related GTP-binding protein Cdc42 [8, 9]
They bind Cdc42 via a Cdc42/Rac interactive binding (CRIB) domain that is present in other Cdc42/Rac effectors, including the PAKs, WASPs (Wiscott-Aldrich syndrome proteins), and MLKs [10]
Summary
The interactions of Cdc42 with its various effector proteins give rise to actin cytoskeletal rearrangements that influence cell shape and motility, as well as stimulate cell-cycle progression and under some conditions, malignant transformation [1,2,3]. 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.
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