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 Blood, 15 December 2007, Vol. 110, No. 13, pp. 4331-4340.
Prepublished online as a Blood First Edition Paper on September 6, 2007; DOI 10.1182/blood-2007-06-094938.

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IMMUNOBIOLOGY

Identification of CMS as a cytosolic adaptor of the human pT{alpha} chain involved in pre-TCR function

María N. Navarro1, Gretel Nusspaumer1, Patricia Fuentes1, Sara González-García1, Juan Alcain1, and María L. Toribio1

1 Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain

The T-cell receptor β (TCRβ)/pre-TCR{alpha} (pT{alpha}) 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 pT{alpha} chain, which suggests the participation of specific intracellular adaptors. However, pT{alpha}-interacting molecules remain unknown. Here, we identified a polyproline-arginine sequence in the human pT{alpha} 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 pT{alpha}, 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 pT{alpha} in traffic to lysosomal degradation. Notably, deletion of the pT{alpha} 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 pT{alpha} intracellular adaptor involved in pre-TCR function.


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Related Article in Blood Online:

CMS links the tail
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Blood 2007 110: 4140-4141. [Full Text] [PDF]





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