CD44 is a type I transmembrane glycoprotein highly polymorphic expressed in most tissues. The single gene can give rise to many different transcripts, named CD44 variants. CD44 represents the principal receptor for the main matrix glycosaminoglucan component, the hyaluronic acid (Ponta et al., 2003). CD44 is a multifunctional protein involved in lymphocyte homing and activation, cell migration or apoptosis. CD44 functions are modulated by metalloproteases that cleave the extracellular part of CD44, giving rise to a soluble form. The remaining transmembrane part of CD44 can be further cleaved by gamma-secretase resulting in the liberation of the C-terminus tail, called CD44ICD (intracellular domain), which translocates to the nucleus. Although, the functions of CD44ICD are not yet understood, it has been shown that it can potentiate its own transcription in a p300/CBP dependant manner (Okamoto et al., 2001). Recent work from Manié and colleagues has shown that CD44ICD per se possesses a transforming activity which is actively participating in the oncogenesis induced by the oncogenic form of Ret MEN2A (Multiple Endocrine Neoplasia type 2A, characterized by medullary carcinoma in the thyroid), revealing a new function for CD44ICD in tumorigenesis (Pelletier et al., 2006). Interestingly, they also observed that CD44ICD potentiates NF-κB transcriptional activity in the context Ret-MEN2A, which is particularly interesting because NF-κB was shown to be an important mediator of cellular transformation by MEN2A (Ludwig et al., 2001) (unpublished data). Finally the group also detected CD44ICD in several human tumoral tissues including colon carcinoma. Altogether these data suggest a new role for CD44 in carnogenesis. The aim of the present project will be to characterize the molecular mechanisms through which CD44ICD promotes cell transformation by investigating the molecular partners and the transcriptional targets of CD44ICD.