CD44 can enter and signal in the nucleus.

Although the cellular adhesion molecule CD44 is involved in processes ranging from lymphocyte homing to tumor metastasis, it has remained unclear how CD44 transduces the intracellular signals required for such a broad range of activities. On page 755, Okamoto et al. propose a surprising mechanism for CD44 signal transduction: a cytoplasmic domain is cleaved from the protein, after which it translocates to the nucleus and acts directly as a transcriptional regulator.

Previous work demonstrated that the extracellular domain of CD44 can be cleaved by membrane-associated proteases, regulating the interaction between CD44 and the extracellular matrix. Okamoto et al. identified a subsequent proteolytic cleavage that releases a fragment of the CD44 intracellular domain (CD44ICD). This fragment translocates to the nucleus, where it activates transcription from the TPA-responsive transcriptional regulation elements found in front of a variety of cellular genes. CD44ICD overexpression also induces CD44 mRNA expression, suggesting a feedback mechanism to regulate CD44 levels. In addition to illuminating the mechanism of CD44 signaling, the new work provides the first example of an adhesion molecule using a type of signal transduction first described for Notch, in which a cleavage fragment of a membrane receptor serves as a transcriptional activator. ▪