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PMID: 21330372 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Stabilization of phosphatidylinositol 4-kinase type IIbeta by interaction with Hsp90.

The Journal of biological chemistry ·Vol. 286 ·No. 14 ·2011-04-08 ·Pages 12775-84

Jung G, Barylko B, Lu D, Shu H, Yin H, Albanesi JP

Abstract

Mammalian cells express two isoforms of type II phosphatidylinositol 4-kinase: PI4KIIα and PI4KIIβ. PI4KIIα exists almost exclusively as a constitutively active integral membrane protein because of its palmitoylation (Barylko, B., Gerber, S. H., Binns, D. D., Grichine, N., Khvotchev, M., Südhof, T. C., and Albanesi, J. P. (2001) J. Biol. Chem. 276, 7705-7708). In contrast, PI4KIIβ is distributed almost evenly between membranes and cytosol. Whereas the palmitoylated membrane-bound pool is catalytically active, the cytosolic kinase is inactive (Wei, Y. J., Sun, H. Q., Yamamoto, M., Wlodarski, P., Kunii, K., Martinez, M., Barylko, B., Albanesi, J. P., and Yin, H. L. (2002) J. Biol. Chem. 277, 46586-46593; Jung, G., Wang, J., Wlodarski, P., Barylko, B., Binns, D. D., Shu, H., Yin, H. L., and Albanesi, J. P. (2008) Biochem. J. 409, 501-509). In this study, we identify the molecular chaperone Hsp90 as a binding partner of PI4KIIβ, but not of PI4KIIα. Geldanamycin (GA), a specific Hsp90 inhibitor, disrupts the Hsp90-PI4KIIβ interaction and destabilizes PI4KIIβ, reducing its half-life by 40% and increasing its susceptibility to ubiquitylation and proteasomal degradation. Cytosolic PI4KIIβ is much more sensitive to GA treatment than is the integrally membrane-associated species. Exposure to GA induces a partial redistribution of PI4KIIβ from the cytosol to membranes and, with brief GA treatments, a corresponding increase in cellular phosphatidylinositol 4-kinase activity. Stimuli such as PDGF receptor activation that also induce recruitment of the kinase to membranes disrupt the Hsp90-PI4KIIβ interaction to a similar extent as GA treatment. These results support a model wherein Hsp90 interacts predominantly with the cytosolic, inactive pool of PI4KIIβ, shielding it from proteolytic degradation but also sequestering it to the cytosol until an extracellular stimulus triggers its translocation to the Golgi or plasma membrane and subsequent activation.

MeSH Terms
Animals Benzoquinones/pharmacology COS Cells Chlorocebus aethiops Cycloheximide/pharmacology Electrophoresis, Polyacrylamide Gel HEK293 Cells HSP90 Heat-Shock Proteins/genetics,metabolism HeLa Cells Humans Immunoprecipitation Lactams, Macrocyclic/pharmacology Mass Spectrometry Microscopy, Fluorescence Minor Histocompatibility Antigens Phosphotransferases (Alcohol Group Acceptor)/genetics,metabolism Protein Binding/genetics,physiology Protein Stability/drug effects Rats
Chemicals
Benzoquinones HSP90 Heat-Shock Proteins Lactams, Macrocyclic Minor Histocompatibility Antigens Cycloheximide Phosphotransferases (Alcohol Group Acceptor) phosphatidylinositol phosphate 4-kinase geldanamycin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Jung Gwanghyun
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75239, USA.
Barylko Barbara
Lu Dongmei
Shu Hongjun
Yin Helen
Albanesi Joseph P
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M110.178616
Published
2011-04-08
Epub
2011-00-17
Pages
12775-84
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3069477
Subset
IM
Grants
NIGMS NIH HHS · R01 GM066110 · United States
NIGMS NIH HHS · R01 GM075401 · United States
External Links
PubMed source DOI: 10.1074/jbc.M110.178616 PMC Full Text View journal details
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