Editors' ChoiceSTAT Signaling

No Phosphate, No Problem

Science Signaling  23 Jun 2009:
Vol. 2, Issue 76, pp. ec204
DOI: 10.1126/scisignal.276ec204

The type I transmembrane glycoprotein CD44 regulates such processes as cell growth and survival. CD44 also serves as a marker of cancer stem cells, and both CD44 and its ligand osteopontin are associated with gastric cancers. Although a previous study showed that a CD44 fragment could associate with transcriptional machinery in the nucleus, how CD44 gets to the nucleus and what role it plays there are unclear. Through immunohistochemical and Western blot analyses, Lee et al. found whole CD44 in the nuclei of primary gastric cancers and gastric cancer cells treated with osteopontin, but not in the nuclei of normal gastric cells. Internalized CD44 passed through early endosomes, and a variant of CD44 missing its C terminus failed to internalize. Ectopic expression of CD44 in CD44-deficient cells promoted their proliferation, which was associated with the increased abundance of cyclin D1 mRNA and protein. Chromatin immunoprecipitation assays showed that CD44 associated with the cyclin D1 promoter, and immunofluorescence and immunoprecipitation (IP) assays demonstrated that nuclear CD44 associated with signal transducer and activator of transcription 3 (STAT3) and the p300 acetyltransferase. Activated CD44 bound to STAT3 in the cytosol and then translocated to the nucleus. Activation of CD44 by an antibody to CD44 resulted in the acetylation, but not the phosphorylation, of STAT3, and the abundance of acetylated STAT3 correlated with the abundance of p300. The expression of other STAT3-responsive genes was also increased in response to activation of CD44. Together, these data suggest that activation of CD44 triggers the acetylation and activation of STAT3, which leads to the expression of proliferation-associated genes in a phospho-independent manner.

J.-L. Lee, M.-J. Wang, J.-Y. Chen, Acetylation and activation of STAT3 mediated by nuclear translocation of CD44. J. Cell Biol. 185, 949–957 (2009). [Abstract] [Full Text]