p56 lck}, LFA-1 and PI3K but not SHP-2 interact with GM1- or GM3-enriched microdomains in a CD4-p56 lck} association-dependent manner

Christiane Barbat , Maylis Trucy , Maurizio Sorice , Tina Garofalo , Valeria Manganelli , Alain Fischer , Fabienne Mazerolles (1)

1 Hôpital Necker - Enfants Malades [AP-HP]

We previously showed that the association of CD4 and GM3 ganglioside induced by CD4 ligand binding was required for the down-regulation of adhesion and that aggregation of ganglioside-enriched domains was accompanied by transient colocalization of LFA-1, PI3K and CD4. We also showed that these proteins co-localized with the GM1 ganglioside that partially co-localized with GM3 in these domains. In this study, we show that CD4/p56 lck} association in CD4 signaling is required for the redistribution of p56 lck}, PI3K, LFA-1 in ganglioside-enriched domains, since ganglioside aggregation and recruitment of these proteins were not observed in a T cell line (A201) expressing the mutant form of CD4 that does not bind p56 lck}. In addition, we show that although these proteins associated in different ways with GM1 and GM3, all of the associations were dependent on CD4/p56 lck} association. Gangliosides could associate with these proteins that differ in affinity binding and could be modified following CD4 signaling. Our data suggest that through these associations, gangliosides transiently sequestrate these proteins and consequently inhibit LFA-1-dependent adhesion. Furthermore, while structural diversity of gangliosides may allow association with distinct proteins, we show that the tyrosine phosphatase SHP-2 also required for the down-regulation of LFA-1-dependent adhesion transiently and partially co-localized with PI3K and p56 lck} in detergent-insoluble membranes without association with GM1 or GM3. We propose that CD4 ligation and binding with p56 lck} and their interaction with GM3 and/or GM1 gangliosides induce recruitment of distinct proteins important for CD4 signaling to form a multimolecular signaling complex.

Mots clés: Life Sciences

Domaines: Biochimie, Biologie Moléculaire

Christiane Barbat, Maylis Trucy, Maurizio Sorice, Tina Garofalo, Valeria Manganelli, et al.. p56 lck}, LFA-1 and PI3K but not SHP-2 interact with GM1- or GM3-enriched microdomains in a CD4-p56 lck} association-dependent manner. Biochemical Journal, 2006, 402 (3), pp.471-481. ⟨10.1042/BJ20061061⟩. ⟨hal-00478630⟩