Cripto antagonism of activin and tgf-b signaling

Abstract

Cripto, a developmental oncoprotein, antagonizes activin and TGF-b signaling by forming a complex with activin and TGF-b and their type II receptors. This complex precludes the formation of a functional activin/TGF-b•type II•type I complex, thereby blocking the signaling of activin and TGF-b. Cripto may be generally capable of blocking antiproliferative Smad2/3 signals and provides a novel mechanism of oncogenic action with multiple therapeutic implications. Inhibiting the formation of Cripto and activin/TGF-b complex may enhance antiproliferative effects of activin and TGF-b.

1 .- 27 . (canceled) 
     
     
         28 . A method of antagonizing Cripto signaling in a cell to reduce the cell's proliferation comprising contacting the cell with an amount of an antibody that targets the Epidermal Growth Factor (EGF)-like domain of Cripto and the Cripto, FRL-1, Cryptic (CFC) domain of Cripto, wherein the antibody is effective to antagonize Cripto signaling to thereby reduce the cell's proliferation. 
     
     
         29 . The method of  claim 28 , wherein the antibody is a human or humanized antibody. 
     
     
         30 . The method of  claim 29 , wherein the antibody is comprised in a pharmaceutical composition. 
     
     
         31 . The method of  claim 28 , wherein the cell is a breast, colon, stomach, pancreas, lung, ovary, endometrial, testis, bladder, or prostate cell. 
     
     
         32 . The method of  claim 31 , wherein the cell is a cancer cell. 
     
     
         33 . A method of antagonizing Cripto signaling in a cell to reduce the cell's proliferation comprising contacting the cell with an amount of a molecule that binds to Cripto and is effective to antagonize Cripto signaling to thereby reduce the cell's proliferation, wherein the molecule is selected from Lefty and Tomoregulin.