Editors' ChoiceProteolysis

Just Like Notch

STKE  09 Apr 2002:
Vol. 2002, Issue 127, pp. tw134
DOI: 10.1126/stke.2002.127.tw134

The membrane proteins Notch and amyloid β-protein precursor (APP) are both cleaved within a transmembrane domain by the γ-secretase activity of presenilins. Although it is known that the released intracellular fragment of Notch translocates to the nucleus to bind transcription factors and to regulate gene expression, it is not known whether the APP intracellular domain (AICD) has a signaling role. Leissring et al. report a correlation between the generation of AICDs and intracellular calcium transients in cultured fibroblasts. By blocking AICD production through γ-secretase inhibitors or by using APP-null or presenilin-null fibroblasts, the authors show that release of calcium from intracellular stores in response to stimulation with bradykinin correlated with the generation of AICDs. The results suggest that released AICD could be a signaling molecule that regulates calcium-dependent processes.

M. A. Leissring, M. P. Murphy, T. R. Mead, Y. Akbari, M. C. Sugarman, M. Jannatipour, B. Anliker, U. Muller, P. Saftig, B. De Strooper, M. S. Wolfe, T.E. Golde, F. M. LaFerla, A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP. Proc. Natl. Acad. Sci. U.S.A. 99, 4697-4702 (2002). [Abstract] [Full Text]