Document Detail

E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity.
MedLine Citation:
PMID:  22763434     Owner:  NLM     Status:  MEDLINE    
E3 ubiquitin ligase Cbl-b plays a crucial role in T cell activation and tolerance induction. However, the molecular mechanism by which Cbl-b inhibits T cell activation remains unclear. Here, we report that Cbl-b does not inhibit PI3K but rather suppresses TCR/CD28-induced inactivation of Pten. The elevated Akt activity in Cbl-b(-/-) T cells is therefore due to heightened Pten inactivation. Suppression of Pten inactivation in T cells by Cbl-b is achieved by impeding the association of Pten with Nedd4, which targets Pten K13 for K63-linked polyubiquitination. Consistent with this finding, introducing Nedd4 deficiency into Cbl-b(-/-) mice abrogates hyper-T cell responses caused by the loss of Cbl-b. Hence, our data demonstrate that Cbl-b inhibits T cell activation by suppressing Pten inactivation independently of its ubiquitin ligase activity.
Hui Guo; Guilin Qiao; Haiyan Ying; Zhenping Li; Yixia Zhao; Yanran Liang; Lifen Yang; Stanley Lipkowitz; Josef M Penninger; Wallace Y Langdon; Jian Zhang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell reports     Volume:  1     ISSN:  2211-1247     ISO Abbreviation:  Cell Rep     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-09-24     Completed Date:  2013-04-17     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101573691     Medline TA:  Cell Rep     Country:  United States    
Other Details:
Languages:  eng     Pagination:  472-82     Citation Subset:  IM    
Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/BC032851;  BC138813;  NM008960
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MeSH Terms
Adaptor Proteins, Signal Transducing / deficiency,  genetics,  metabolism*
Antigens, CD28 / metabolism
Endosomal Sorting Complexes Required for Transport / deficiency,  genetics,  metabolism*
Lymphocyte Activation / physiology
Mice, Inbred BALB C
Mice, Knockout
Models, Animal
Molecular Sequence Data
PTEN Phosphohydrolase / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-cbl / deficiency,  genetics,  metabolism*
Receptors, Antigen, T-Cell / metabolism
Signal Transduction / physiology
T-Lymphocytes / metabolism*,  pathology
Ubiquitin-Protein Ligases / deficiency,  genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Antigens, CD28; 0/Endosomal Sorting Complexes Required for Transport; 0/Receptors, Antigen, T-Cell; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Proteins c-akt; EC protein, mouse; EC Phosphohydrolase; EC 6.3.2.-/Proto-Oncogene Proteins c-cbl; EC protein, mouse; EC ubiquitin protein ligases; EC Ligases

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