Nore1B regulates TCR signaling via Ras and Carma1

Abstract

Nore1A was originally identified as a potential Ras effector, and Nore1B is an alternatively spliced isoform. Both share a Ras/Rap association domain (RA domain) but only Nore1A contains sequence motifs that predict SH3 domain binding and diacylglycerol/phorbol ester binding in the amino-terminal region. Here we report that Carma1 binds to Nore1A and Nore1B through the RA domain and that Carma1 interacts with active Ras in the presence of Nore1B. RNA interference against Nore1B attenuates NF-κB activation induced by T cell receptor (TCR) ligation, but not NF-κB activation induced by TNFα or lipoteichoic acid. In addition, Nore1B is also required for KiRas GV12-mediated ERK1 activation and Elk1 reporter activity in T cells. We also provide evidence that knockdown of Nore1B also impairs polarized redistribution of Ras at the B cell-T cell immune interface. Together, these findings suggest that endogenous Nore1B recruits active Ras to the APC-T cell interface and mediates the interaction between Ras and Carma1.

Differential requirement for CARMA1 in agonist‐selected T‐cell development

“…Deficiency in Bcl10 or IKK2 may have more dramatic effects on TCR signaling, which then leads to the broader array of T‐cell subset deficiency. An alternative explanation for the differences between the changes seen in CARMA1 −/− mice and other TCR signaling protein‐deficient mice may be interactions of CARMA1 with other TCR‐induced signaling pathways or related proteins 14, 42–44. We also cannot completely rule out an effect from CARMA1 in non‐TCR‐induced signaling pathways 45, 46, although these have not been well described.…”

RASSF tumor suppressor gene family: Biological functions and regulation

“…Required for apoptosis and growth inhibition [8] Inhibits MST2 activity [93] Modulates the MAP kinase signal downstream of the Ras signal [77] K-Ras [8] ST1, MST2 [177] MST1 [75] Not available 5A (Nore1A) 1q32 47.1 kDa Suppresses tumour growth via apoptosis induction or cell cycle delay [7,82] Regulates microtubule formation [182] Induces degradation of HIPK1 oncoprotein [183] Required for the TNFa mediated apoptosis and full activation of MST1 [80] Ras, Carma1 [182,184] MST1 [43,177] MST2 [177] tubulin, Aurora A [182] Mdm2 [183] Itch [185] Yes [80] resistant to TNFa-induced apoptosis, fail to activate Mst1 in vivo 5C (Nore1B, RAPL) 1q32 30.4 kDa Regulates lymphocyte adhesion, T cell migration, T cell receptor regulation [84,86,186] Controls the directional migration of vascular endothelial cells [6] Ras, Carma1 [184] Rap1, Rap2, MST1 [6,84,86,186] Yes [86] impaired lymphocyte trafficking and lymphoid organ abnormalities 6 4q13 43.4 kDa arising from alternative splicing and differential promoter usage. Among the RASSF1 subtypes, 1A and 1C are the most extensively studied members with both localized to microtubules and involved in regulation of growth and migration [14,15].…”

“…Required for apoptosis and growth inhibition [8] Inhibits MST2 activity [93] Modulates the MAP kinase signal downstream of the Ras signal [77] K-Ras [8] ST1, MST2 [177] MST1 [75] Not available 5A (Nore1A) 1q32 47.1 kDa Suppresses tumour growth via apoptosis induction or cell cycle delay [7,82] Regulates microtubule formation [182] Induces degradation of HIPK1 oncoprotein [183] Required for the TNFa mediated apoptosis and full activation of MST1 [80] Ras, Carma1 [182,184] MST1 [43,177] MST2 [177] tubulin, Aurora A [182] Mdm2 [183] Itch [185] Yes [80] resistant to TNFa-induced apoptosis, fail to activate Mst1 in vivo 5C (Nore1B, RAPL) 1q32 30.4 kDa…”

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

“…[101, 109-111], [93], [90], [112], [113], [114], [90, 115], [116], [117], [118], [119-121],[​122,​123] , [124], [125], [126], [127, 128], [129], [83, 130], [131], [132, 133], [134, 135], [136], [84], [137-139], [140, 141], [142, 143], [144], [145], [146]…”