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J. Biol. Chem., Vol. 280, Issue 16, 15700-15708, April 22, 2005

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Regulation and Function of the Sonic Hedgehog Signal Transduction Pathway in Isolated Gastric Parietal Cells^*

Vinzenz Stepan, Saravanan Ramamoorthy, Hildegard Nitsche, Yana Zavros, Juanita L. Merchant, and Andrea Todisco

From the Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Shh (Sonic hedgehog) regulates gastric epithelial cell differentiation. We reported that incubation of purified canine parietal cells with epidermal growth factor (EGF) for 6–16 h, stimulates H⁺/K⁺-ATPase -subunit gene expression through the activation of Akt. We explored if Shh mediates some of the actions of EGF in the parietal cells. EGF induced a 6-fold increase in Shh expression, measured by Western blots, after 5 h of incubation. This effect was inhibited by both the phosphatidylinositol 3-kinase inhibitor LY294002 and by transduction of the cells with an adenoviral vector expressing dominant negative Akt. EGF stimulated the release of Shh-like immunoreactivity from the parietal cells, after 16 h of incubation. Shh induced H⁺/K⁺-ATPase -subunit gene expression, assessed by Northern blots, it stimulated a luciferase reporter plasmid containing the EGF-responsive sequence (ERE) of the canine H⁺/K⁺-ATPase -subunit gene promoter, and it induced parietal cell nuclear protein binding to the ERE. Gli transcription factors mediate the intracellular actions of Shh. Co-transfection of the parietal cells with the H⁺/K⁺-luc plasmid together with one expressing Gli2, induced H⁺/K⁺-luciferase activity 5-fold, whereas co-transfection of the cells with the H⁺/K⁺-luc plasmid together with one expressing dominant negative Gli2, inhibited EGF induction of H⁺/K⁺-luciferase activity. Identical results were observed in the presence of the Shh signal transduction pathway inhibitor, cyclopamine. Transfection of the cells with dominant negative Akt inhibited EGF, but not Shh stimulation of H⁺/K⁺-ATPase-luciferase activity. Thus, EGF but not Shh signals through Akt. Preincubation of the cells for 16 h with either Shh or EGF enhanced histamine-stimulated [¹⁴C]aminopyrine uptake by 50%. In conclusions, some of the actions of EGF in the parietal cells are mediated by the sequential activation of the Akt and the Shh signal transduction pathways. These effects might represent novel mechanisms mediating the actions of growth factors on gastric epithelial cell differentiation.

Received for publication, November 18, 2004 , and in revised form, January 27, 2005.

^* This work was supported in part by NIDDK, National Institutes of Health (NIH) Grants RO1-DK-058312 (to A. T.), PO1-DK-062041 (to A. T. and J. L. M.), and RO1-DK-1410 (to J. L. M.) and by funds from the National Organization for Rare Disorders (NORD) (to A. T.), and the University of Michigan Gastrointestinal Peptide Research Center (NIH Grant P30-DK-34933). 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.

Recipient of a Pilot Feasibility Grant DK-34933 from the Gastrointestinal Peptide Research Center.

To whom correspondence should be addressed: Dept. of Internal Medicine, University of Michigan Medical Center, 6520 MSRB I, Ann Arbor, MI 48109-0682. Tel.: 734-647-2942; Fax: 734-763-2535; E-mail: atodisco{at}umich.edu.

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