Ubiquitin-proteasome degradation of serum- and glucocorticoid-regulated kinase-1 (SGK-1) is mediated by the chaperone-dependent E3 ligase CHIP.
SGK-1 (serum- and glucocorticoid-regulated kinase-1) is a stress-induced serine/threonine kinase that is phosphorylated and activated downstream of PI3K (phosphoinositide 3-kinase). SGK-1 plays a critical role in insulin signalling, cation transport and cell survival. SGK-1 mRNA expression is transiently induced following cellular stress, and SGK-1 protein levels are tightly regulated by rapid proteasomal degradation. In the present study we report that SGK-1 forms a complex with the stress-associated E3 ligase CHIP [C-terminus of Hsc (heat-shock cognate protein) 70-interacting protein]; CHIP is required for both the ubiquitin modification and rapid proteasomal degradation of SGK-1. We also show that CHIP co-localizes with SGK-1 at or near the endoplasmic reticulum. CHIP-mediated regulation of SGK-1 steady-state levels alters SGK-1 kinase activity. These data suggest a model that integrates CHIP function with regulation of the PI3K/SGK-1 pathway in the stress response.
Belova
Larissa
L
Department of Medicine and Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA.
Sharma
Sanjay
S
Brickley
Deanna R
DR
Nicolarsen
Jeremy R
JR
Patterson
Cam
C
Conzen
Suzanne D
SD
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse