| Research Abstract |
Cell surface adhesion molecules are crucial for the migratory process, as they couple interactions with the extracellular matrix (ECM) to the cytoskeletal apparatus inside the cell. CD44 is the principal cell adhesion receptor for several extracellular matrix components, mainly hyaluronic acid which is abundant in brain tissue. We found that CD44 expressed in cancer cells is proteolytically cleaved at the ectodomain through membrane-anchored metalloproteases under various physiological conditions including calcium influx, activation of PKC and activation of Ras proto-oncogene product. We found that this cleavage is responsible for dynamic regulation of the interaction between CD44 and the extracellular matrix and plays a critical role in cancer cell migration. In the present study, we found that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (CD44ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate (TPA) responsive element (TRE), which is found in numerous genes involved in diverse cellular processes. We demonstrate that CD44ICD potentiates transactivation mediated by the transcriptional coactivator CBP/p300. Furthermore, we show that the CD44 gene is one of the potential targets for transcriptional activation by CD44ICD. These observations establish a novel signaling pathway that links proteolytic processing of an adhesion molecule at the cell surface to transcriptional activation in the nucleus. Therefore, CD44 can be a novel molecular target for prevention of glioma invasion.
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