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J. Biol. Chem., Vol. 278, Issue 50, 50791-50802, December 12, 2003

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CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3- Subunit of the T Cell Antigen Receptor^*

Pilar Muñoz, María-del-Carmen Navarro¶, Esther J. Pavón||, Javier Salmerón**, Fabio Malavasi, Jaime Sancho, and Mercedes Zubiaur

From the Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, 18001 Granada, the ^**Hospital Universitario San Cecilio, 18012 Granada, Spain, and the Laboratory of Immunogenetics, University of Torino Medical School, 10126 Torino, Italy

In this study we present data supporting that most CD38 is pre-assembled in a subset of Brij 98-resistant raft vesicles, which were stable at 37 °C, and have relatively high levels of Lck and the CD3- subunit of T cell antigen receptor-CD3 complex in contrast with a Brij 98-soluble pool, where CD38 is associated with CD3-, and Lck is not detected. Our data further indicate that following CD38 engagement, LAT and Lck are tyrosinephosphorylated exclusively in Brij 98-resistant rafts, and some key signaling components translocate into rafts (i.e. Sos and p85-phosphatidylinositol 3-kinase). Moreover, N-Ras results activated within rafts immediately upon CD38 ligation, whereas activated Erk was mainly found in soluble fractions with delayed kinetics respective to Ras activation. Furthermore, full phosphorylation of CD3- and CD3- only occurs in rafts, whereas partial CD3- tyrosine phosphorylation occurs exclusively in the soluble pool, which correlated with increased levels of c-Cbl tyrosine phosphorylation in the non-raft fractions. Taken together, these results suggest that, unlike the non-raft pool, CD38 in rafts is able to initiate and propagate several activating signaling pathways, possibly by facilitating critical associations within other raft subsets, for example, LAT rafts via its capacity to interact with Lck and CD3-. Overall, these findings provide the first evidence that CD38 operates in two functionally distinct microdomains of the plasma membrane.

Received for publication, July 23, 2003 , and in revised form, September 22, 2003.

^* This work was supported in part by Instituto Carlos III-FIS, Ministerio de Sanidad y Consumo Grant 01/1073, Consejería de Salud de la Junta de Andalucía Grant 209/02 (to M. Z.), CICYT Grants SAF99-0024 and SAF2002-00721 (to J. Sancho), AIRC (Milano, Italy), TELETHON (Roma, Italy), Biotecnologia (CNR, Roma, Italy), and by the AIDS and TB projects (ISS, Rome, Italy) (to F. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Fellowship I3P from Fondo Social Europeo and Fellowship FPI from the Ministerio de Ciencia y Tecnología, Spain.

^¶ Supported by Contract I3P from Fondo Social Europeo.

^|| Supported by Fellowship from CICYT Grant SAF2002-00721.

Supported by a Contrato de Investigadores del Plan Nacional de Salud from the Ministerio de Sanidad y Consumo, and a contract of the program "Ramón y Cajal" from the Ministerio de Ciencia y Tecnología, Spain. To whom correspondence should be addressed: Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, Ventanilla, 11, 18001 Granada, Spain. Tel.: 34-958805182; Fax: 34-958203911; E-mail: mzubiaur{at}ipb.csic.es.

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