Editors' ChoiceDevelopment

Proteolytic Morphogen Switch

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Science's STKE  27 Nov 2001:
Vol. 2001, Issue 110, pp. tw439
DOI: 10.1126/stke.2001.110.tw439

The bone morphogenic protein (BMP; a member of the transforming growth factor-β family) is a key regulator of dorsoventral patterning during development, and its signaling is therefore subject to complex regulation. Binding of the Chordin protein to BMP inhibits binding of BMP to its receptor, and this interaction is influenced by the zinc metalloproteinase Tolloid, which can cleave Chordin and enhance BMP signaling. Precisely how this works has been a mystery, however, because Chordin fragments still bind to BMP and inhibit its signaling. Larraín et al. now show that twisted gastrulation (Tsg), another protein that binds to Chordin and forms a ternary complex with BMP, may act as part of a critical switch to control BMP signaling. Their results help to explain how Tsg has been shown, in various circumstances, either to enhance or inhibit BMP signaling. Larraín et al. altered expression of Tsg in Xenopus embryos and used in vitro analysis of binding interactions to confirm that Tsg inhibits BMP signaling by forming a ternary complex with Chordin and BMP that inhibits receptor binding more effectively than does Chordin alone. However, once Chordin is cleaved by the Tolloid protease, Tsg's effect becomes a stimulatory one. The Chordin fragments still inhibit receptor binding by BMP, but in this case, binding of Tsg to the fragments blunted their inhibitory effects and caused enhanced degradation of the fragments. The authors propose that, depending on the concentrations of the various components in particular cells, the proteolytic switching of Tsg from an inhibitor to an activator of BMP signaling may result in formation of the abrupt boundaries characteristic of pattern formation during embryogenesis.

J. Larraín, M. Oelgeschläger, N. I. Ketpura, B. Reversade, L. Zakin, E. M. De Robertis, Proteolytic cleavage of Chordin as a switch for the dual activities of Twisted gastrulation in BMP signaling. Development 128, 4439-4447 (2001). [Online Journal]