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Cell reports
May 31, 2012;1 (5): 472-82.

E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells 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
Author Information
  1. Hui Guo: Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
PMID: 22763434 DOI: 10.1016/j.celrep.2012.04.008

Abstract

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.

Associated Data

GENBANK | BC032851; BC138813; NM008960

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Grants

  1. R01 AI090901/NIAID NIH HHS
  2. R01 AR049775/NIAMS NIH HHS
  3. R01AR049775/NIAMS NIH HHS
  4. AI090901/NIAID NIH HHS

MeSH Term

Adaptor Proteins, Signal Transducing
Animals
CD28 Antigens
Endosomal Sorting Complexes Required for Transport
Female
Lymphocyte Activation
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Models, Animal
Molecular Sequence Data
Nedd4 Ubiquitin Protein Ligases
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-cbl
Receptors, Antigen, T-Cell
Signal Transduction
T-Lymphocytes
Ubiquitin-Protein Ligases

Chemicals

Adaptor Proteins, Signal Transducing
CD28 Antigens
Cblb protein, mouse
Endosomal Sorting Complexes Required for Transport
Receptors, Antigen, T-Cell
Nedd4 Ubiquitin Protein Ligases
Nedd4l protein, mouse
Proto-Oncogene Proteins c-cbl
Ubiquitin-Protein Ligases
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
Pten protein, mouse
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 2

Word Cloud

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