USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor.
The stability and membrane localization of the transforming growth factor-β (TGF-β) type I receptor (TβRI) determines the levels of TGF-β signalling. TβRI is targeted for ubiquitylation-mediated degradation by the SMAD7-SMURF2 complex. Here we performed a genome-wide gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of TGF-β signalling. USP4 was found to directly interact with TβRI and act as a deubiquitylating enzyme, thereby controlling TβRI levels at the plasma membrane. Depletion of USP4 mitigates TGF-β-induced epithelial to mesenchymal transition and metastasis. Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4. AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability. Moreover, AKT-induced breast cancer cell migration was inhibited by USP4 depletion and TβRI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-β and AKT signalling pathways.
Department of Molecular Cell Biology, Leiden University Medical Center, Postbus 9600 2300 RC Leiden, The Netherlands.
Long
L
Zhang
FangFang
F
Zhou
Yvette
Y
Drabsch
Rui
R
Gao
B Ewa
BE
Snaar-Jagalska
Craig
C
Mickanin
Huizhe
H
Huang
Kelly-Ann
KA
Sheppard
Jeff A
JA
Porter
Chris X
CX
Lu
Peter
P
ten Dijke
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D004795:Enzyme Stability; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009361:Neoplasm Invasiveness; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination; D015027:Zebrafish / Q000196:embryology
D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C486203:USP4 protein, human; C082325:Usp4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077293:Receptor, Transforming Growth Factor-beta Type I; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases