Interaction of activated Cdc42-associated tyrosine kinase ACK2 with HSP90.
ACK2 (activated Cdc42-associated tyrosine kinase 2) is a specific downstream effector for Cdc42, a member of the Rho family of small G-proteins. ACK2 interacts with clathrin, an endocytic vesicle coating protein, and SH3PX1, a sorting nexin, and is involved in clathrin-mediated endocytosis. While searching for proteins that interact with ACK2, we found that HSP90 (heat-shock protein 90) binds to ACK2. Analysis of a series of truncation mutants of ACK2 has defined the regions within the kinase domain of ACK2 that are required for binding to HSP90. The binding of HSP90 to ACK2 is blocked upon treatment with geldanamycin, an HSP90-specific ATPase inhibitor, and is required for the in vivo kinase activity of ACK2 and its association with Cdc42. Overall, our data suggest a novel mechanism of regulation in which HSP90 serves as a regulatory component in an ACK2 functional complex and plays a role in sustaining its kinase activity.
Yang
Wannian
W
Weis Center for Research, Geisinger Clinic, 100 North Academy Ave., Danville, PA 17822, USA. wyang1@geisinger.edu
Jansen
Jaclyn M
JM
Lin
Qiong
Q
Canova
Sabrina
S
Cerione
Richard A
RA
Childress
Chandra
C
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D019556:COS Cells / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology; D010770:Phosphotransferases / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D018841:HSP90 Heat-Shock Proteins; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000251:Adenosine Triphosphatases; D020764:cdc42 GTP-Binding Protein