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Journal of Cell Science 115, 433-443 (2002)
© 2002 The Company of Biologists Limited

Research Article

Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes

Alix Delaguillaumie1, Cécile Lagaudrière-Gesbert*, Michel R. Popoff2 and Hélène Conjeaud1,{ddagger}

1 U332 – Institut National de la Santé et la Recherche Médicale. Institut Cochin de Génétique Moléculaire, 22 rue Méchain, 75014 Paris, France
2 Toxines Microbiennes, Institut Pasteur, 28 rue du Dr Roux 75724 Paris Cedex15, France
* Present address: Harvard Medical School, Dept of Pathology, D2-143, 200 Longwood Avenue, Boston MA-02115, USA

{ddagger}Author for correspondence (e-mail: conjeaud{at}cochin.inserm.fr)

Accepted October 15, 2001

Activation of T lymphocytes requires the engagement of the T-cell receptor and costimulation molecules through cell-to-cell contacts. The tetraspanin CD82 has previously been shown to act as a cytoskeleton-dependent costimulation molecule. We show here that CD82 engagement leads to the tyrosine phosphorylation and association of both the Rho GTPases guanosine exchange factor Vav1 and adapter protein SLP76, suggesting that Rho GTPases participate in CD82 signaling. Indeed, broad inactivation of all Rho GTPases, or a specific blockade of RhoA, Rac1 or Cdc42, inhibited the morphological changes linked to CD82 engagement but failed to modulate the inducible association of CD82 with the actin network. Rho GTPase inactivation, as well as actin depolymerization, reduced the ability of CD82 to phosphorylate Vav and SLP76 and to potentiate the phosphorylation of two early TcR signaling intermediates: the tyrosine kinases ZAP70 and membrane adapter LAT. Taken together, this suggests that an amplification loop, via early Vav and SLP76 phosphorylations and Rho-GTPases activation, is initiated by CD82 association with the cytoskeleton, which permits cytoskeletal rearrangements and costimulatory activity. Moreover, the involvement of CD82 in the formation of the immunological synapse is strongly suggested by its accumulation at the site of TcR engagement. This novel link between a tetraspanin and the Rho GTPase cascade could explain why tetraspanins, which are known to form heterocomplexes, are involved in cell activation, adhesion, growth and metastasis.

Key words: Tetraspanin, TM4SF, CD82, Rho GTPases, Cytoskeleton, T lymphocytes, Costimulation




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© The Company of Biologists Ltd 2002