Editors' ChoiceONCOGENESIS

The Leading Edge of Transformation?

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Science's STKE  25 Oct 2005:
Vol. 2005, Issue 307, pp. tw380
DOI: 10.1126/stke.3072005tw380

Nakatani et al. purified complexes containing the tumor suppressor RB (retinoblastoma protein, which was stably expressed in a tagged form in HeLa cells) and identified p600 [a target of the human papilloma virus-16 oncoprotein E7 (HPV-16 E7)], calmodulin, and several other proteins. Far-Western analysis in the presence or absence of Ca2+ indicated that p600 bound directly to Ca2+-bound calmodulin. Immunofluorescence analysis of human foreskin fibroblasts showed that p600 was localized in meshwork structures in both nucleus and cytoplasm. RB, found mostly in the nucleus, was localized near nuclear p600 in patterns suggesting that p600 and RB might act as a chromatin scaffold. Cytoplasmic p600 formed meshwork structures with clathrin at the leading edge of membrane protrusion sites, with calmodulin and the inositol 1,4,5-trisphosphate receptor localized close to p600. Cells in which p600 expression was suppressed with short hairpin RNA showed decreased activation of focal adhesion kinase (FAK, a protein implicated in integrin-mediated cell survival pathways), defective formation of membrane ruffles, and increased susceptibility to apoptosis. The existence of a cytoplasmic pool of p600 led the authors to conclude that its cytoplasmic functions and role in regulating integrin-mediated signaling were likely independent of RB. They further suggest that, given p600's targeting by HPV-16 E7, the data may imply a link between events occurring at the leading edge of the cell membrane and viral transformation.

Y. Nakatani, H. Konishi, A. Vassilev, H. Kurooka, K. Ishiguro, J.-I. Sawada, T. Ikura, S. J. Korsmeyer, J. Qin, A. M. Herlitz, p600, a unique protein required for membrane morphogenesis and cell survival. Proc. Natl. Acad. Sci. U.S.A. 102, 15093-15098 (2005). [Abstract] [Full Text]

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