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 soluble extracellular domain (ECD) of Activin receptor-Like Kinase 4 (ALK4). 
     
     
         29 . The soluble ALK4-ECD of  claim 28 , wherein the ALK-4 ECD is human ALK4-ECD. 
     
     
         30 . The soluble ALK4-ECD of  claim 28 , wherein the ALK4-ECD comprises a mutation at one or more positions selected from the group consisting of amino acid position 70, 75 and 77. 
     
     
         31 . The soluble ALK4-ECD of  claim 30 , wherein the ALK4-ECD comprises an alanine at one or more positions selected from the group consisting of amino acid position 70, 75 and 77. 
     
     
         32 . The soluble ALK4-ECD of  claim 30 , wherein the ALK4-ECD comprises a mutation at amino acid position 75. 
     
     
         33 . The soluble ALK4-ECD of  claim 32 , wherein the mutation comprises an alanine at amino acid position 75. 
     
     
         34 . The soluble ALK4-ECD of  claim 30 , wherein the ALK4-ECD comprises mutations at amino acid positions 70, 75, and 77. 
     
     
         35 . A method of decreasing cell proliferation comprising contacting the cell with an effective amount of a soluble ALK4-ECD of  claim 28 , wherein proliferation of the cell is decreased. 
     
     
         36 . The method of  claim 35 , wherein the cell is derived from an organ selected from the group consisting of breast, colon, stomach, pancreas, lung, ovary, endometrial, testis, bladder and prostate. 
     
     
         37 . The method of  claim 36 , wherein the cell is a tumor cell or a cancer cell. 
     
     
         38 . The method of  claim 37 , wherein the tumor cell or cancer cell is a breast tumor cell or breast cancer cell. 
     
     
         39 . The method of  claim 38 , wherein the breast tumor cell or breast cancer cell is contacted with a soluble ALK4-ECD comprising an alanine at amino acid position 75.