Introduction: Activin and TGFβ are members of the TGFβ superfamily with growth suppressive and pro-migratory properties. While growth suppressive SMAD 2/3/4 signaling is shared, we have evidence of diverging SMAD-independent migratory signaling involving the CDK inhibitor p21. Here, we dissect the participation of respective mitogenic pathways in activin and TGFβ-specific SMAD-independent signaling in colon cancer. Methods: Colon cancer cell lines with and without SMAD4 were assessed for SMAD, PI3K and MEK pathway influences on activin or TGFβ signaling and associated effects using pharmacologic inhibition, knock-down, co-immunoprecipitation, Western blotting, and functional assays of migration. Results: Irrespective of SMAD4 status, activin-induced migration was PI3K-dependent and associated with PI3K-induced p21 downregulation, while TGFβ-induced migration was MEK1/2-dependent. Activin but not TGFβ lead to colocalization of ACVR1, ACVR2's primary binding partner, with p85, the regulatory subunit of PI3K, in an ACVR1-dependent SMAD-independent manner. Further, activin-induced p21 downregulation was PI3K dependent and associated with proteasomal degradation, while TGFβ stabilized p21 via MEK/ERK. Inhibition of proteasomal degradation of p21 lead to a decrease in migration with activin implicating p21 downregulation in activin-induced migration but not in TGFβ-induced migration. Conclusion: Activin and TGFβ diverge in their pro-migratory SMAD-independent signaling in colon cancer affecting distinct targets to include p21 and employing diverse mitogenic signals. Dissecting ligand-specific functions in colon cancer may be exploited for risk stratification or therapeutic intervention in the near future.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3252. doi:1538-7445.AM2012-3252