BMP Receptors Keep SANE During Development

Science's STKE  07 Jan 2003:
Vol. 2003, Issue 164, pp. tw11-TW11
DOI: 10.1126/stke.2003.164.tw11

Raju et al. used a yeast two-hybrid screen for proteins binding to Xenopus Smad1 and identified SANE (Smad1 antagonistic effector), a novel protein with sequence similarity to nuclear envelope proteins. SANE bound to type I bone morphogenetic protein (BMP) receptors, as well as to Smad1, and inhibited BMP signaling. BMPs, members of the transforming growth factor-β (TGF-β) family, help regulate bone formation, neural cell fate determination, and embryonic patterning during development. BMPs bind to a receptor complex containing type I and type II receptors, which leads to phosphorylation of Smads1 and 5 and Smad translocation to the nucleus. The authors used Western analysis of Smad1 immunoprecipitates to confirm that SANE interacted with Smad1 in Xenopus embryos and to show that Smad1 did not bind to a SANE mutant lacking the COOH-terminus. SANE also bound to Smad5. SANE mRNA injected into Xenopus embryos specifically blocked BMP signaling, whereas the SANE mutant that did not bind Smad1 did not. SANE also blocked BMP-stimulated osteoblastic differentiation in cultured mouse C2C12 cells. SANE reduced Smad1 phosphorylation in embryos derived from fertilized eggs injected with BMP-4 mRNA and inhibited BMP-4-dependent nuclear translocation of Smad1 in NIH 3T3 cells. Western analysis of SANE immunoprecipitates indicated that SANE also bound to BMP type I receptors; unlike SANE binding to Smad1, this interaction did not require the SANE COOH-terminus. These data suggest that SANE is an inhibitor of BMP signaling with a novel mechanism that involves interaction with both the BMP receptor and pathway-specific Smads.

G. P. Raju, N. Dimova, P. S. Klein, H.-C. Huang, SANE, a novel LEM domain protein, regulates bone morphogenetic protein signaling through interaction with Smad1. J. Biol. Chem. 278, 428-437 (2003). [Abstract] [Full Text]