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J. Biol. Chem., Vol. 280, Issue 2, 1024-1036, January 14, 2005

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Role of Rho/ROCK and p38 MAP Kinase Pathways in Transforming Growth Factor--mediated Smad-dependent Growth Inhibition of Human Breast Carcinoma Cells in Vivo^*

Anil K. Kamaraju and Anita B. Roberts

From the Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892-5055

TGF- is a multifunctional cytokine known to exert its biological effects through a variety of signaling pathways of which Smad signaling is considered to be the main mediator. At present, the Smad-independent pathways, their interactions with each other, and their roles in TGF--mediated growth inhibitory effects are not well understood. To address these questions, we have utilized a human breast cancer cell line MCF10CA1h and demonstrate that p38 MAP kinase and Rho/ROCK pathways together with Smad2 and Smad3 are necessary for TGF--mediated growth inhibition of this cell line. We show that Smad2/3 are indispensable for TGF--mediated growth inhibition, and that both p38 and Rho/ROCK pathways affect the linker region phosphorylation of Smad2/3. Further, by using Smad3 mutated at the putative phosphorylation sites in the linker region, we demonstrate that phosphorylation at Ser²⁰³ and Ser²⁰⁷ residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways. We demonstrate that activation of the p38 MAP kinase pathway is necessary for the full transcriptional activation potential of Smad2/Smad3 by TGF-, whereas activity of Rho/ROCK is necessary for both down-regulation of c-Myc protein and up-regulation of p21^waf1 protein, directly interfering with p21^waf1 transcription. Our results not only implicate Rho/ROCK and p38 MAPK pathways as necessary for TGF--mediated growth inhibition, but also demonstrate their individual contributions and the basis for their cooperation with each other.

Received for publication, April 9, 2004 , and in revised form, October 21, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Data.

To whom correspondence should be addressed: Laboratory of Cell Regulation and Carcinogenesis, Bldg. 41, Rm. C629, 41 Library Dr., MSC 5055, NCI, National Institutes of Health, Bethesda, MD 20892-5055. Tel.: 301-496-5391; Fax: 301-496-8395; E-mail: robertsa{at}dce41.nci.nih.gov.

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