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J. Biol. Chem., Vol. 280, Issue 37, 32209-32217, September 16, 2005

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Cross-talk between Bone Morphogenetic Protein and Transforming Growth Factor- Signaling Is Essential for Exendin-4-induced Insulin-positive Differentiation of AR42J Cells^*

From the Department of Surgery Research, The Children's Mercy Hospital, Kansas City, Missouri 64108

A key goal of cellular engineering is to manipulate progenitor cells to become -cells, allowing cell replacement therapy to cure diabetes mellitus. As a paradigm for cell engineering, we have studied the molecular mechanisms by which AR42J cells become -cells. Bone morphogenetic proteins (BMPs), implicated in a myriad of developmental pathways, have not been well studied in insulin-positive differentiation. We found that the canonical intracellular mediators of BMP signaling, Smad-1 and Smad-8, were significantly elevated in AR42J cells undergoing insulin-positive differentiation in response to exendin-4 treatment, suggesting a role for BMP signaling in -cell formation. Similarly, endogenous BMP-2 ligand and ALK-1 receptor (activin receptor-like kinase-1; known to activate Smads 1 and 8) mRNAs were specifically up-regulated in exendin-4-treated AR42J cells. Surprisingly, Smad-1 and Smad-8 levels were suppressed by the addition of BMP-soluble receptor inhibition of BMP ligand binding to its receptor. Here, insulin-positive differentiation was also ablated. BMP-2 ligand antisense also strongly inhibited Smad-1 and Smad-8 expression, again with the abolition of insulin-positive differentiation. These results demonstrate a previously unrecognized key role for BMP signaling in mediating insulin-positive differentiation through the intracellular Smad signaling pathway. In short, BMP signaling may represent a novel downstream target of exendin-4 (glucagon-like peptide 1) signaling and potentially serve as an upstream regulator of transforming growth factor- isoform signaling to differentiate the acinar-like AR42J cells into insulin-secreting cells.

Received for publication, May 18, 2005 , and in revised form, July 8, 2005.

^* This work was supported by National Institutes of Health Grants 1 R01 DK58400-01 and 1 R01 DK064952-01 to (G. K. G.) and Grant JDRF1 2-1999-636. 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.

¹ To whom correspondence should be addressed: Children's Hospital of Pittsburgh, 3705 5th Ave., Pittsburgh, PA 15213. Tel.: 412-692-7283; E-mail: george.gittes{at}chp.edu.

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