70Z/3 Cbl induces PLCγ1 activation in T lymphocytes via an alternate Lat- and Slp-76-independent signaling mechanism

Graham, Laurie; Verı́, Maria-Concetta; DeBell, Karen E.; Noviello, C.; Rawat, Rashmi; Jen, Sandy; Bonvini, Ezio; Rellahan, Barbara L.

doi:10.1038/sj.onc.1206318

Cited by 5 publications

(1 citation statement)

References 49 publications

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“…The authors attribute the difference to the presence of a yet unknown LAT-replacing adaptor which is absent in Jurkat-cell lines. Indeed, the importance of LAT-independent TCR-signaling has been recognized previously (7,20,25,38,(43)(44)(45)(46). CD6 is known to recruit SLP-76, Gads, Grb2, Vav1 and SHIP1 independently of LAT (20,47,48), and is therefore a potential candidate for LAT-independent Itk phosphorylation and Calcium flux.…”

Section: Lat Inborn Errors Of Immunitymentioning

confidence: 96%

The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt From Inborn Errors of Immunity

et al. 2021

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Adaptor molecules lack enzymatic and transcriptional activities. Instead, they exert their function by linking multiple proteins into intricate complexes, allowing for transmitting and fine-tuning of signals. Many adaptor molecules play a crucial role in T-cell signaling, following engagement of the T-cell receptor (TCR). In this review, we focus on Linker of Activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 KDa (SLP-76). Monogenic defects in these adaptor proteins, with known roles in T-cell signaling, have been described as the cause of human inborn errors of immunity (IEI). We describe the current knowledge based on defects in cell lines, murine models and human patients. Germline mutations in Adhesion and degranulation adaptor protein (ADAP), have not resulted in a T-cell defect.

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Section: Lat Inborn Errors Of Immunitymentioning

confidence: 96%

The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt From Inborn Errors of Immunity

et al. 2021

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The Cbl interactome and its functions

Schmidt

Đikić

2005

Nat Rev Mol Cell Biol

364

392

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Cbl proteins are ubiquitin ligases and multifunctional adaptor proteins that are implicated in the regulation of signal transduction in various cell types and in response to different stimuli. Cbl-associated proteins can assemble together at a given time or space inside the cell, and such an interactome can form signal competent networks that control many physiological processes. Dysregulation of spatial or temporal constraints in the Cbl interactome results in the development of human pathologies such as immune diseases, diabetes and cancer.

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c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1

Meyer

Husain

2011

Oncogene

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Angiogenesis is regulated by highly coordinated action of various proteins with pro- and anti-angiogenic functions. Among the many cytoplasmic signaling proteins that are activated by VEGFR-2, activation of PLCγ1 is considered to play a pivotal role in angiogenic signaling. In previous study we have identified c-Cbl as a negative regulator of PLCγ1 in endothelial cells, the biochemical and biological significance of c-Cbl, however, in angiogenesis in vivo and molecular mechanisms involved were remained elusive. Here we report that genetic inactivation of c-Cbl in mice results in enhanced tumor angiogenesis and retinal neovascularization. Endothelial cells derived from c-Cbl null mice displayed elevated cell proliferation and tube formation in response to VEGF stimulation. Loss of c-Cbl also resulted in robust activation of PLCγ1 and increased intracellular calcium release. c-Cbl-dependent ubiquitination selectively inhibited tyrosine phosphorylation of PLCγ1 and mostly refrain it from ubiquitin-mediated degradation. Hence, we propose c-Cbl as an angiogenic suppressor protein where upon activation it uniquely modulates PLCγ1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis.

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70Z/3 Cbl induces PLCγ1 activation in T lymphocytes via an alternate Lat- and Slp-76-independent signaling mechanism

Cited by 5 publications

References 49 publications

The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt From Inborn Errors of Immunity

The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt From Inborn Errors of Immunity

The Cbl interactome and its functions

c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1

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