Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway

CD44 is a widely distributed cell surface adhesion molecule and is implicat ed in diverse biological processes. However, the nature of intracellular si gnaling triggered by CD44 remains to be elucidated. Here, we show that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellu lar domain, resulting in the release of a CD44 intracellular domain (ICD) f ragment. Consequently, CD44ICD acts as a signal transduction molecule, wher e it translocates to the nucleus and activates transcription mediated throu gh the 12-O-tetradecanoylphorbol 13-acetate-responsive element, which is fo und in numerous genes involved in diverse cellular processes. Expression of an uncleavable CD44 mutant as well as metalloprotease inhibitor treatment blocks CD44-mediated transcriptional activation. In search of the underlyin g mechanism, we have found that CD44ICD potentiates transactivation mediate d by the transcriptional coactivator CBP/p300. Furthermore, we show that ce lls expressing CD44ICD produce high levels of CD44 messenger RNA, suggestin g that the CD44 gene is one of the potential targets for transcriptional ac tivation by CD44ICD. These observations establish a novel CD44 signaling pa thway and shed new light on the functional link between proteolytic process ing of an adhesion molecule at the cell surface and transcriptional activat ion in the nucleus.