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CD44's nuclear road trip

STAT3 (red) waits in the cytosol (left) but hitches a ride into the nucleus with CD44 (right).

Lee et al. reveal how a characteristic surface marker for cancer stem cells triggers abnormal growth. The protein makes a dash for the nucleus, picking up a couple of accomplices, including the transcription activator STAT3, along the way.

The surface receptor CD44 is overexpressed in many tumor types, including stomach cancer. Responding to neighboring cells and the extracellular matrix, the protein helps control everything from differentiation to survival. At the membrane, CD44 promotes signaling through the integrin proteins by corralling lipid rafts. Other scientists had previously shown that a snippet of CD44 could turn on genes in the nucleus. But whether the full-length protein could get there and what functions it might perform once it arrived were uncertain.

Lee et al. found that after stimulation, CD44 molecules evacuate the membrane of stomach cancer cells via the endocytic pathway. The proteins wend through the cytosol and eventually slip into the nucleus through a nuclear pore. A mutant protein lacking the nuclear localization sequence was locked out of the nucleus. But CD44 doesn't travel solo. On the way, it links up with STAT3 and another protein, p300. This meeting leads to STAT3's acetylation and activation. Once the combo reaches the nucleus, it latches onto the promoter for the cyclin D1 gene, which nudges the cell from the G1 phase into the S phase, thus speeding cell division. Other cancer-related surface receptors such as EGFR migrate into the nucleus. But they exert their effects through their enzymatic activity, whereas CD44 serves as a scaffold for other proteins, the researchers say. Still a mystery is how CD44's mobility relates to its role as a cancer stem cell marker.

References

Lee, J.-L., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200812060.[CrossRef]

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Acetylation and activation of STAT3 mediated by nuclear translocation of CD44

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This Article Full Text (PDF, 565K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Leslie, M. PubMed Articles by Leslie, M. Related Collections Related Article Social Bookmarking                            What's this?