T cell-to-T cell clustering enhances NF-κB activity by a PI3K signal mediated by Cbl-b and Rho

Herndon, Thomas M.; Pirone, Dana M.; Tsokos, George C.; Chen, Christopher

doi:10.1016/j.bbrc.2005.05.064

Cited by 8 publications

(5 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ubiquitylation of p85, instead of promoting degradation of PI‐3′K, inhibits recruitment of p85 to CD28 and TCR (Fang et al, 2000; Fang and Liu, 2001). Consistent with these data, Cbl‐b has also been shown to inhibit the PI‐3′K‐dependent activation of NF‐κB in T cells (Herndon et al, 2005). Similarly, ubiquitylation of another Cbl interactor, CrkL, does not affect its stability, but inhibits its interaction with C3G (Shao et al, 2003; Zhang et al, 2003).…”

Section: Mechanisms Of Effectssupporting

confidence: 54%

The Cbl family proteins: Ring leaders in regulation of cell signaling

Swaminathan

Tsygankov

2006

Journal Cellular Physiology

280

349

View full text Add to dashboard Cite

The proto-oncogenic protein c-Cbl was discovered as the cellular form of v-Cbl, a retroviral transforming protein. This was followed over the years by important discoveries, which identified c-Cbl and other Cbl-family proteins as key players in several signaling pathways. c-Cbl has donned the role of a multivalent adaptor protein, capable of interacting with a plethora of proteins, and has been shown to positively influence certain biological processes. The identity of c-Cbl as an E3 ubiquitin ligase unveiled the existence of an important negative regulatory pathway involved in maintaining homeostasis in protein tyrosine kinase (PTK) signaling. Recent years have also seen the emergence of novel regulators of Cbl, which have provided further insights into the complexity of Cbl-influenced pathways. This review will endeavor to provide a summary of current studies focused on the effects of Cbl proteins on various biological processes and the mechanism of these effects. The major sections of the review are as follows: Structure and genomic organization of Cbl proteins; Phosphorylation of Cbl; Interactions of Cbl; Localization of Cbl; Mechanism of effects of Cbl: (a) Ubiquitylation-dependent events: This section elucidates the mechanism of Cbl-mediated downregulation of EGFR and details the PTK and non-PTKs targeted by Cbl. In addition, it addresses the functional requirements for E3 Ubiquitin ligase activity of Cbl and negative regulation of Cbl-mediated downregulation of PTKs, (b) Adaptor functions: This section discusses the mechanisms of adaptor functions of Cbl in mitogen-activated protein kinase (MAPK) activation, insulin signaling, regulation of Ras-related protein 1 (Rap1), PI-3 0 kinase signaling, and regulation of Rho-family GTPases and cytoskeleton; Biological functions: This section gives an account of the diverse biological functions of Cbl and includes the role of Cbl in transformation, T-cell signaling and thymus development, B-cell signaling, mast-cell degranulation, macrophage functions, bone development, neurite growth, platelet activation, muscle degeneration, and bacterial invasion; Conclusions and perspectives.

show abstract

Section: Mechanisms Of Effectssupporting

confidence: 54%

The Cbl family proteins: Ring leaders in regulation of cell signaling

Swaminathan

Tsygankov

2006

Journal Cellular Physiology

280

349

View full text Add to dashboard Cite

show abstract

“…However, LY294002 did not affect the IL-23-stimulated phosphorylation of IB-␣. The signal transduction associated with NF-B is generally known in terms of PI3K/Akt (30,31). However, our results imply that the activation of PI3K/Akt caused by IL-23 is not directly associated with NF-B activation, but that the activation of PI3K/Akt may activate signal transduction molecules such as AP-1 and STAT3 (32,33).…”

Section: Cd4contrasting

confidence: 53%

STAT3 and NF-κB Signal Pathway Is Required for IL-23-Mediated IL-17 Production in Spontaneous Arthritis Animal Model IL-1 Receptor Antagonist-Deficient Mice

Cho

Kang

Moon

et al. 2006

The Journal of Immunology

287

196

View full text Add to dashboard Cite

IL-23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 has proinflammatory activity, inducing IL-17 secretion from activated CD4+ T cells and stimulating the proliferation of memory CD4+ T cells. We investigated the pathogenic role of IL-23 in CD4+ T cells in mice lacking the IL-1R antagonist (IL-1Ra−/−), an animal model of spontaneous arthritis. IL-23 was strongly expressed in the inflamed joints of IL-1Ra−/− mice. Recombinant adenovirus expressing mouse IL-23 (rAd/mIL-23) significantly accelerated this joint inflammation and joint destruction. IL-1β further increased the production of IL-23, which induced IL-17 production and OX40 expression in splenic CD4+ T cells of IL-1Ra−/− mice. Blocking IL-23 with anti-p19 Ab abolished the IL-17 production induced by IL-1 in splenocyte cultures. The process of IL-23-induced IL-17 production in CD4+ T cells was mediated via the activation of Jak2, PI3K/Akt, STAT3, and NF-κB, whereas p38 MAPK and AP-1 did not participate in the process. Our data suggest that IL-23 is a link between IL-1 and IL-17. IL-23 seems to be a central proinflammatory cytokine in the pathogenesis of this IL-1Ra−/− model of spontaneous arthritis. Its intracellular signaling pathway could be useful therapeutic targets in the treatment of autoimmune arthritis.

show abstract

“…It is well known that the NFκB pathway is required for the production of TNF-α, IL-6 and MCP-1 so it appears that sequences in Cbl-b are involved in regulating the activity of this pathway. However the only published connection to date linking Cbl-b and the NFκB pathway is in T cells where Cbl-b overexpression was found to inhibit NFκB induction in a PI 3-kinase dependent manner (Herndon et al, 2005). It was hypothesized that this inhibitory effect was mediated by Cbl-bdirected ubiquitylation of p85, the regulatory subunit of PI 3-kinase.…”

Section: Discussionmentioning

confidence: 99%

The Cbl-b RING finger domain has a limited role in regulating inflammatory cytokine production by IgE-activated mast cells

Oksvold

Dagger

Thien

et al. 2008

Molecular Immunology

View full text Add to dashboard Cite

The RING finger type E3 ubiquitin ligase, Cbl-b, is abundantly expressed in bone marrow-derived mast cells (BMMCs) and functions as a potent negative regulator of signalling responses from the high-affinity IgE receptor (FcvarepsilonRI). To determine the contribution of Cbl-b E3 ligase activity we generated knockin mice with a loss-of-function mutation in the RING finger domain. We find the mice to be healthy and, unlike equivalent c-Cbl RING finger mutant mice, produce homozygous offspring at the expected frequency. Comparative analyses of BMMCs from Cbl-b knockout and Cbl-b RING finger mutant mice revealed that both showed similarly enhanced FcvarepsilonRI signalling compared to wild-type cells for most parameters examined. A notable exception was a markedly higher level of activation of IkappaB kinase (IKK) in Cbl-b knockout BMMC compared to RING finger mutant-derived cells. In addition BMMCs from the Cbl-b RING finger mutant did not retard FcvarepsilonRI internalization to the extent observed for knockout cells. Most striking however was the finding that RING finger mutant mast cells do not produce the very high levels of TNF-alpha, IL-6, and MCP-1 evident in Cbl-b knockout cultures following FcvarepsilonRI activation. Thus the ability of Cbl-b to function as a negative regulator of FcvarepsilonRI signalling that promotes inflammatory cytokine production is largely independent of the RING finger domain.

show abstract

T cell-to-T cell clustering enhances NF-κB activity by a PI3K signal mediated by Cbl-b and Rho

Cited by 8 publications

References 30 publications

The Cbl family proteins: Ring leaders in regulation of cell signaling

The Cbl family proteins: Ring leaders in regulation of cell signaling

STAT3 and NF-κB Signal Pathway Is Required for IL-23-Mediated IL-17 Production in Spontaneous Arthritis Animal Model IL-1 Receptor Antagonist-Deficient Mice

The Cbl-b RING finger domain has a limited role in regulating inflammatory cytokine production by IgE-activated mast cells

Contact Info

Product

Resources

About