Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function.
Saccharomyces WEE1 (Swe1), the only "true" tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1(Wee1) phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90alpha) in the N domain of Hsp90. Phosphorylation is cell-cycle associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Nonphosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific posttranslational modification of a unique subcellular pool of the chaperone, and they provide a strategy to increase the cellular potency of Hsp90 inhibitors.
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Mehdi
M
Mollapour
Shinji
S
Tsutsumi
Alison C
AC
Donnelly
Kristin
K
Beebe
Mari J
MJ
Tokita
Min-Jung
MJ
Lee
Sunmin
S
Lee
Giulia
G
Morra
Dimitra
D
Bourboulia
Bradley T
BT
Scroggins
Giorgio
G
Colombo
Brian S
BS
Blagg
Barry
B
Panaretou
William G
WG
Stetler-Stevenson
Jane B
JB
Trepel
Peter W
PW
Piper
Chrisostomos
C
Prodromou
Laurence H
LH
Pearl
Len
L
Neckers
D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D019281:Dimerization; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism*; D054875:Ubiquitination
D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D014443:Tyrosine; C099685:SWE1 protein, S cerevisiae; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D046988:Proteasome Endopeptidase Complex