CD44 mediates the responses of cells to their microenvironment and participates in the regulation of growth, survival, differentiation, and motility (Al-Hajj et al., 2003; Ponta et al., 2003; Ponti et al., 2005). Several cell surface receptors, including EGF receptor family members, are known to migrate to the nucleus as an intact polypeptide or a proteolytic fragment with or without their corresponding ligands. These nuclear localized receptors have been shown to act as transcription factors (Lin et al., 2001; Ni et al., 2001; Wang et al., 2004) for genes like cyclin D1 (Lin et al., 2001), FGF2 (Peng et al., 2001), and COX-2 (Wang et al., 2004) or modulators for induction of c-jun and cyclin D1 (Reilly and Maher, 2001). Although phosphorylation is a crucial posttranslational modification that regulates the activities of different proteins, there are many others, including acetylation (Yang and Seto, 2007), isgylation (Kim and Zhang, 2005), methylation (D’Alessio et al., 2007), sumoylation (Zhao, 2007), and ubiquitination (Giandomenico et al., 2003). Function-related posttranslational modifications of STAT3 in response to treatment with cytokine or growth factor include phosphorylation on tyrosine 705 and serine 727 residues. However, unphosphorylated or tyrosinemutated STAT3 can still form dimers and induce transcription (Braunstein et al., 2003). Others have found that STAT3 dimerization is regulated by reversible acetylation of lysine at residue 685 in the SH2 domain of STAT3 (Yuan et al., 2005). IL-6–induced acetylation of the STAT3 N terminus is necessary for acutephase induction of angiotensinogen (Ray et al., 2002). Together, these observations indicate that site-specific acetylation of STAT3 is an important regulatory modification that influences protein–protein interaction and transcriptional regulation. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal transduction processes. A previous study has shown that a fragment of CD44 can directly interact with the transcriptional machinery, resulting in the up-regulation of genes containing the TPA-responsive element, including CD44 itself (Kajita et al., 2001). However, the mechanism of their nuclear import and the function of nuclear CD44 are virtually unknown. In this study, we show for the first time that full-length CD44 is internalized and translocated into the nucleus, where, in complex with STAT3 and p300, it binds to the cyclin D1 promoter and enhances cell proliferation.