Signal Pharmaceuticals, Inc.

Hsc Research and Development Limited Partnership

Hsc Research and Development Limited

Jeffrey Wrana

Gerald H Thomsen

Stephen W Scherer

Liliana Attisano

This invention provides unique members of the Hect family of ubiquitin ligases that specifically target BMP and TGF&#x3b2;/activin pathway-specific Smads. The novel ligases have been named Smurf1 and Smurf2. They directly interact with Smads1 and 5 and Smad7, respectively, and regulate the ubiquitination, turnover and activity of Smads and other proteins of these pathways. Smurf1 interferes with biological responses to BMP, but not activin signaling. In amphibian embryos Smurf1 inhibits endogenous BMP signals, resulting in altered pattern formation and cell fate specification in the mesoderm and ectoderm. The present invention provides a unique regulatory link between the ubiquitination pathway and the control of cell fate determination by the TGF&#x3b2; superfamily during embryonic development. Thus, Smurf1 is a negative regulator of Smad1 signal transduction, by targeting Smad1, Smurf1 blocks BMP signaling. In mammalian cells, Smurf2 suppresses TGF&#x3b2; signalling, and in, blocks formation of dorsal mesoderm and causes anterior truncation of the embryos. Smurf2 forms a stable complex with Smad7, which induces degradation and downregulation of TGF&#x3b2;/activin signalling.

Modulators of Smurf and BMP/TGF&#x3b2; signaling pathways

A new family of proteins, the SARA proteins, has been identified. These proteins bind to receptor-regulated Smad proteins and modulate signal transduction by TGF&#x3b2;, activin and bone morphogenetic protein.

SARA proteins

A new human gene, MADR2, has been cloned and sequenced, and has been identified as a tumour suppressor gene. The protein encoded by the gene, MADR2, has been shown to participate in the TGF.beta. signalling pathway and to be phosphorylated on stimulation of the TGF.beta. receptor.

Growing community of inventors

Toronto, Canada

Jeffrey Wrana