Getting to the Nucleus--More Cleavage!

Science's STKE  04 Dec 2001:
Vol. 2001, Issue 111, pp. tw440
DOI: 10.1126/stke.2001.111.tw440

Functional regulation of some cell-surface molecules involves their enzymatic cleavage at the plasma membrane to release soluble ectodomain fragments into the extracellular milieu. Accumulating evidence also indicates that intracellular cleavage is a key regulatory mechanism. Okamoto et al. report this to be the case with a widely expressed adhesion molecule, CD44. Cleavage of the ectodomain by a metalloprotease is followed by intracellular cleavage, perhaps by γ-secretase. Activation of gene transcription induced by CD44 was prevented when a form of CD44 not subject to intracellular cleavage was expressed in Cos7 cells. When overexpressed in transfected cells, the intracellular domain fragment localized to the nucleus, and potentiated transcription of a reporter gene in cooperation with two transcriptional coactivators, CREB-binding protein and p300. Hence, adhesion molecules join the repertoire of cell-surface proteins that appear to regulate gene expression through fragments that are transported to the nucleus where they interact directly with the transcriptional machinery.

I. Okamoto, Y. Kawano, D. Murakami, T. Sasayama, N. Araki, T. Miki, A. J. Wong, H. Saya, Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. J. Cell Biol. 155, 755-762 (2001). [Abstract] [Full Text]