In:
Blood, American Society of Hematology, Vol. 110, No. 13 ( 2007-12-15), p. 4331-4340
Abstract:
The T-cell receptor β (TCRβ)/pre-TCRα (pTα) pre-TCR complex (pre-TCR) signals the expansion and differentiation of de-veloping thymocytes. Functional pro-perties of the pre-TCR rely on its unique pTα chain, which suggests the participation of specific intracellular adaptors. However, pTα-interacting molecules remain unknown. Here, we identified a polyproline-arginine sequence in the human pTα cytoplasmic tail that interacted in vitro with SH3 domains of the CIN85/CMS family of adaptors, and mediated the recruitment of multiprotein complexes involving all (CMS, CIN85, and CD2BP3) members. Supporting the physiologic relevance of this interaction, we found that 1 such adaptor, CMS, interacted in vivo with human pTα, and its expression was selectively up-regulated during human thymopoiesis in pre-TCR–activated thymocytes. Upon activation, pre-TCR clustering was induced, and CMS and polymerized actin were simultaneously recruited to the pre-TCR activation site. CMS also associated via its C-terminal region to the actin cytoskeleton in the endocytic compartment, where it colocalized with internalized pTα in traffic to lysosomal degradation. Notably, deletion of the pTα CIN85/CMS-binding motif impaired pre-TCR–mediated Ca2+ mobilization and NFAT transcriptional activity, and precluded activation induced by overexpression of a CMS-SH3 N-terminal mutant. These results provide the first molecular evidence for a pTα intracellular adaptor involved in pre-TCR function.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2007-06-094938
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2007
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
