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J. Biol. Chem., Vol. 281, Issue 34, 24247-24253, August 25, 2006

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MAPKAPK-2 Is a Critical Signaling Intermediate in NHE3 Activation Following Na⁺-Glucose Cotransport^*

Zhihong Hu, Yingmin Wang, W. Vallen Graham, Liping Su, Mark W. Musch, and Jerrold R. Turner¹

From the Departments of Pathology and Medicine, University of Chicago, Chicago, Illinois 60637

Villus enterocyte nutrient absorption occurs via precisely orchestrated interactions among multiple transporters. For example, transport by the apical Na⁺-glucose cotransporter, SGLT1, triggers translocation of NHE3, Na⁺-H⁺ antiporter isoform 3, to the plasma membrane. This translocation requires activation of p38 mitogen-activated protein kinase (MAPK), Akt2, and ezrin. Akt2 directly phosphorylates ezrin, but the precise role of p38 MAPK in this process remains to be defined. Sequence analysis suggested that p38 MAPK could not directly phosphorylate Akt2. We hypothesized that MAPKAPK-2 might link p38 MAPK and Akt2 activation. MAPKAPK-2 was phosphorylated after initiation of Na⁺-glucose cotransport with kinetics that paralleled activation of p38 MAPK, Akt2, and ezrin. MAPKAPK-2, Akt2, and ezrin phosphorylation were all attenuated by p38 MAPK inhibition but were unaffected by dominant negative ezrin expression. Akt2 inhibition blocked ezrin but not p38 MAPK or MAPKAPK-2 phosphorylation, suggesting that MAPKAPK-2 could be an intermediate in p38 MAPK-dependent Akt2 activation. Consistent with this, MAP-KAPK-2 could phosphorylate an Akt2-derived peptide in vitro. siRNA-mediated MAPKAPK-2 knockdown inhibited phosphorylation of Akt2 and ezrin but not p38 MAPK. MAPKAPK-2 knockdown also blocked NHE3 translocation. Thus, MAP-KAPK-2 controls Akt2 phosphorylation. In so doing, MAP-KAPK-2 links p38 MAPK to Akt2, ezrin, and NHE3 activation after SGLT1-mediated transport.

Received for publication, March 28, 2006 , and in revised form, June 16, 2006.

^* This work was supported by National Institutes of Health Grants DK61931 and DK68271, University of Chicago Digestive Disease Center Grant DK42086, and University of Chicago Cancer Center Grant CA14599. 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: Dept. of Pathology, The University of Chicago, 5841 South Maryland Ave., MC 1089, Chicago, IL 60637. Tel.: 773-702-2433; E-mail: jturner{at}bsd.uchicago.edu.

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