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J. Biol. Chem., Vol. 280, Issue 27, 25920-25927, July 8, 2005

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Disabled-2 (Dab2) Mediates Transforming Growth Factor (TGF)-stimulated Fibronectin Synthesis through TGF-activated Kinase 1 and Activation of the JNK Pathway^*

Barbara A. Hocevar, Celine Prunier, and Philip H. Howe

From the Department of Cell Biology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195

The multifunctional cytokine transforming growth factor (TGF) exerts many of its effects through its regulation of extracellular matrix components, including fibronectin (FN). Although expression of both TGF and FN are essential for embryonic development and wound healing in the adult, overexpression leads to excessive deposition of extracellular matrix observed in many fibroproliferative disorders. We previously have demonstrated that TGF-stimulated FN induction requires activation of the c-Jun N-terminal kinase (JNK) pathway; however, the signaling molecules that link the TGF receptors to the JNK pathway remain unknown. We show here that the cytosolic adaptor protein disabled-2 (Dab2) directly stimulates JNK activity, whereas stable small interfering RNA-mediated ablation of Dab2 in NIH3T3 mouse fibroblasts and A10 rat aortic smooth muscle cells demonstrates that its expression is required for TGF-mediated FN induction. We demonstrate that TGF treatment stimulates the association of Dab2 with the mitogen-activated protein kinase kinase kinase, TAK1. Attenuation of cellular TAK1 levels by transient double-stranded RNA oligonucleotide transfection as well as overexpression of kinase-deficient TAK1 leads to abrogation of TGF-stimulated FN induction. Furthermore, cell migration, another JNK-dependent response, is attenuated in NIH3T3-siDab2-expressing clones. We, therefore, delineate a signaling pathway proceeding from the TGF receptors to Dab2 and TAK1, leading to TGF-stimulated JNK activation, FN expression, and cell migration.

Received for publication, February 1, 2005 , and in revised form, May 11, 2005.

^* This work was supported by NCI, National Institutes of Health Grants CA55536 and CA80095 (to P. H. H.) and a Scientist Development Grant from the American Heart Association (to B. A. H.). 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.

Present address: Dept. of Pharmacology and Toxicology, Indiana University School of Medicine, Medical Science Bldg., MS A419, 635 Barnhill Dr., Indianapolis, IN 46202.

To whom correspondence should be addressed: Dept. of Cell Biology, NC-1, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Tel.: 216-445-9750; Fax: 216-444-9404; E-mail: howep{at}ccf.org.

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