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J. Biol. Chem., Vol. 281, Issue 3, 1725-1730, January 20, 2006

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erbB1 Functions as a Sensor of Airway Epithelial Integrity by Regulation of Protein Phosphatase 2A Activity^*

Paola D. Vermeer, Lacey Panko, Michael J. Welsh¶, and Joseph Zabner1

From the Department of Internal Medicine, ^¶Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 and Program in Forensic Science, University of Nebraska, Lincoln, Nebraska 68588

Two enzymes, protein phosphatase 2A and atypical protein kinase C, are associated with the tight junction and regulate its function. For example, phosphorylation of the tight junction protein occludin is required for its incorporation into the junction. The association of a kinase and phosphatase with the tight junction suggests that a balance between their activities exists and is required for normal tight junction function. This hypothesis predicts that loss of epithelial integrity may disrupt this balance in such a way as to facilitate restoration of epithelial integrity. Our previous data have shown that apically localized growth factors segregate from their basolaterally localized erbB receptors. Loss of epithelial integrity allows ligand access to the basolateral membrane where it immediately binds to and activates erbB receptors. We found that activation of erbB1 leads to phosphorylation of protein phosphatase 2A, inhibiting its activity. Importantly, this phosphorylation event was dependent on factors in the overlying airway surface liquid; washing away this liquid prevented phosphorylation. erbB1-mediated inhibition of phosphatase activity would shift the balance in favor of the kinase such that tight junction proteins would regain their phosphorylation, allowing for their incorporation into the junction complex. This mechanism provides a rapid means of sensing the loss of epithelial integrity and subsequently restoring barrier function.

Received for publication, June 27, 2005 , and in revised form, October 12, 2005.

^* This work was supported by National Institutes of Health Grants K01 DK60113-01 and R01 HL075276-01A1. 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: University of Iowa Roy J. and Lucille A. Carver College of Medicine, 440 EMRB, Iowa City, IA 52242. Tel.: 319-335-7608; Fax: 319-335-7623; E-mail: joseph-zabner{at}uiowa.edu.

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