E3 Ubiquitin Ligase Cbl-b Regulates Pten via Nedd4 in T Cells Independently of Its Ubiquitin Ligase Activity

Guo, Hui; Qiao, Guilin; Ying, Haiyan; Li, Zhenping; Zhao, Yixia; Liang, Yanran; Yang, Lifen; Lipkowitz, Stanley; Penninger, Josef; Langdon, Wallace Y.; Zhang, Jian

doi:10.1016/j.celrep.2012.04.008

Cited by 68 publications

(70 citation statements)

References 49 publications

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“…Decreased p85 ubiquitination and increased PI3= kinase activity may explain the hyper-activation of Cbl-b knockout T cells and consequent autoimmunity, but p85 degradation may not be involved (73,74). Cbl-b also regulates the phosphatase PTEN, independently of its ubiquitin ligase activity (75). These results suggest ubiquitin-independent and degradation-independent effects of both c-Cbl and Cbl-b.…”

Section: Substrates and Functions Of Cblmentioning

confidence: 88%

Cell Regulation by Phosphotyrosine-Targeted Ubiquitin Ligases

Cooper

Kaneko

2015

Molecular and Cellular Biology

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Three classes of E3 ubiquitin ligases, members of the Cbl, Hakai, and SOCS-Cul5-RING ligase families, stimulate the ubiquitination of phosphotyrosine-containing proteins, including receptor and nonreceptor tyrosine kinases and their phosphorylated substrates. Because ubiquitination frequently routes proteins for degradation by the lysosome or proteasome, these E3 ligases are able to potently inhibit tyrosine kinase signaling. Their loss or mutational inactivation can contribute to cancer, autoimmunity, or endocrine disorders, such as diabetes. However, these ligases also have biological functions that are independent of their ubiquitination activity. Here we review relevant literature and then focus on more-recent developments in understanding the structures, substrates, and pathways through which the phosphotyrosine-specific ubiquitin ligases regulate diverse aspects of cell biology. Phosphorylation and ubiquitination are among the commonest and best-studied posttranslational modifications of proteins. A phosphate group or ubiquitin molecule can trigger or obstruct protein-protein interactions, alter subcellular localization, stabilize a particular protein conformation, or have myriad other effects. Phosphorylation is directly catalyzed by protein kinases, but ubiquitination is more complex, requiring sequential activity of E1, E2, and E3 ubiquitin-activating, -conjugating, and -ligating enzymes (1-5). E3 ubiquitin ligases fall into two major groups: HECT domain ligases receive ubiquitin from an E2 enzyme and transfer it to a bound substrate, while RING-type ligases position an E2-ubiquitin conjugate near a substrate protein to facilitate ubiquitin transfer. Both phosphorylation and ubiquitination are reversible; protein phosphorylation is reversed by protein phosphatases and ubiquitination by deubiquitinating enzymes (DUBs) (6-8). Therefore, both phosphorylation/dephosphorylation and ubiquitination/deubiquitination can allow repeated cycles of protein modification. Reversible ubiquitination is particularly important in DNA repair and NF-B signaling. However, many ubiquitination events lead irreversibly to protein destruction, allowing regulation of protein turnover. For example, K48 polyubiquitin chains primarily route cytosolic proteins to the proteasome, while modification of many Lys residues with single ubiquitin molecules (multimonoubiquitination) has several functions, including routing membrane proteins for destruction in the lysosome (9-11). The irreversibility of proteolysis means that the ubiquitin-proteasome and ubiquitin-lysosome pathways directly control protein life spans.Protein phosphorylation and ubiquitination cross talk at many levels (12). In this review, we focus on situations where phosphorylation of a substrate creates a binding site for an E3 ligase, rendering ubiquitination dependent on prior phosphorylation of that substrate (13). Such phosphorylation-dependent substrate selection has particular importance because it can layer negative feedback onto an otherwise reversible phosphoryla...

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Section: Substrates and Functions Of Cblmentioning

confidence: 88%

Cell Regulation by Phosphotyrosine-Targeted Ubiquitin Ligases

Cooper

Kaneko

2015

Molecular and Cellular Biology

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“…Future studies are needed to determine how TSC1 controls the expression of these molecules. Furthermore, a recent report has demonstrated that Cbl-b prevents T-cell anergy, in part, by suppressing TCR/CD28-induced inactivation of phosphatase and tensin homolog (Pten) to prevent Akt activation (46). Because Akt promotes mTORC1 signaling by inactivating TSC2, it would be interesting to determine whether mTOR signaling is enhanced in Cbl-b-deficient T cells and whether enhanced mTOR signaling may contribute the loss of T-cell tolerance caused by Cbl-b deficiency.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor TSC1 is critical for T-cell anergy

Xie

Lou

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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T-cell anergy is a state of T cells that is hyporesponsive to stimulation via the T-cell receptor and costimulatory molecules and is thought to be important for self-tolerance. How T-cell anergy is regulated is still poorly understood. We report here that tuberous sclerosis (TSC)1 is critical for T-cell anergy. Deficiency of TSC1 resulted in enhanced Tcell proliferation and cytokine production in the absence of cluster of differentiation (CD)28-mediated costimulation, accompanied by enhanced T-cell metabolism. Resistance of TSC1-deficient T cells to anergy is correlated with increased signaling through the mammalian target of rapamycin complex (mTORC)1 and can be reverted by treatment of these cells with mTORC1 inhibitor rapamycin. Expression of the inducible costimulator (ICOS) is increased in TSC1-deficient T cells, which can be inhibited by rapamycin. Simultaneous blockade of both CD28 and ICOS costimulation partially restored sensitivity of TSC1-deficient T cells to anergy induction. Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 signaling through both ICOS-dependent and -independent mechanisms.T-cell activation | signal transduction C oordinated signals from the T-cell receptor (TCR), costimulatory receptors, and cytokine receptors ensure naïve T-cell activation and differentiation to proper effector T cells. T cells can be made anergic by stimulation through their TCR without a costimulatory signal, by stimulation with partial agonist peptides in the presence of costimulation, or by treatment with the Ca 2+ ionophore ionomycin (1-3). Anergic T cells do not respond to antigen restimulation even in the presence of appropriate costimulation. They are impaired in producing cytokines such as IFN-γ or IL-2, defective in proliferative response, and metabolically inert (4-7). T-cell anergy is thought to be important for preventing self-reactive T cells from full activation to trigger autoimmune diseases.The mammalian target of rapamycin (mTOR) integrates numerous environmental stimuli including growth factors, nutrients, and stress-activated signals to regulate cell metabolism, survival, growth, and proliferation (8). mTOR associates with multiple proteins and forms two distinct signaling complexes. mTOR complex (mTORC)1 contains raptor and phosphorylates ribosomal protein s6 kinase, 70-kd, 1 (S6K1) and eukaryotic translation initiation factor 4e-binding protein 1 (4E-BP1) to promote ribosomogenesis and protein translation. The rictor-containing mTORC2 phosphorylates both Akt at serine 473 residue to promote Akt activation and cell survival and PKCθ to promote T-helper (Th)2 differentiation (9, 10). Engagement of the TCR activates both mTORC1 and mTORC2, which is dependent on the RasGRP1-Ras-Erk1/2 pathway and is inhibited by diacylglycerol kinases (11-13). Rapamycin treatment or genetic ablation of mTOR induces T-cell anergy and inhibits helper T-cell differentiation but promotes expansion of natural regulatory T cells (nTregs) and the generation of inducible Tregs (9, 14-...

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“…With regard to posttranslational modifications that regulate PTEN, ubiquitination is of particular interest. It is thought to involve K48-linked polyubiquitination and proteosomal degradation and K63-linked polyubiquitination or monoubiquitination, which were proposed to affect the function and subcellular compartmentalization of PTEN (8)(9)(10).…”

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confidence: 99%

Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth

Hsia¹,

Kumar²,

Lucà

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Protein ubiquitination is a core regulatory determinant of neural development. Previous studies have indicated that the Nedd4-family E3 ubiquitin ligases Nedd4-1 and Nedd4-2 may ubiquitinate phosphatase and tensin homolog (PTEN) and thereby regulate axonal growth in neurons. Using conditional knockout mice, we show here that Nedd4-1 and Nedd4-2 are indeed required for axonal growth in murine central nervous system neurons. However, in contrast to previously published data, we demonstrate that PTEN is not a substrate of Nedd4-1 and Nedd4-2, and that aberrant PTEN ubiquitination is not involved in the impaired axon growth upon deletion of Nedd4-1 and Nedd4-2. Rather, PTEN limits Nedd4-1 protein levels by modulating the activity of mTORC1, a protein complex that controls protein synthesis and cell growth. Our data demonstrate that Nedd4-family E3 ligases promote axonal growth and branching in the developing mammalian brain, where PTEN is not a relevant substrate. Instead, PTEN controls neurite growth by regulating Nedd4-1 expression.

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E3 Ubiquitin Ligase Cbl-b Regulates Pten via Nedd4 in T Cells Independently of Its Ubiquitin Ligase Activity

Cited by 68 publications

References 49 publications

Cell Regulation by Phosphotyrosine-Targeted Ubiquitin Ligases

Cell Regulation by Phosphotyrosine-Targeted Ubiquitin Ligases

Tumor suppressor TSC1 is critical for T-cell anergy

Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth

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