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J. Biol. Chem., Vol. 281, Issue 24, 16453-16461, June 16, 2006

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Keratin 20 Serine 13 Phosphorylation Is a Stress and Intestinal Goblet Cell Marker^*

Qin Zhou¹, Monique Cadrin, Harald Herrmann^¶, Che-Hong Chen, Robert J. Chalkley^||, Alma L. Burlingame^||, and M. Bishr Omary²

From the Department of Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304 and Stanford University Digestive Disease Center, Stanford, California 94305, University of Quebec at Trois-Rivieres, Quebec G9A 5H7, Canada, ^||University of California, San Francisco, California 94143, and the ^¶German Cancer Research Center, D69120 Heidelberg, Germany

Keratin polypeptide 20 (K20) is an intermediate filament protein with preferential expression in epithelia of the stomach, intestine, uterus, and bladder and in Merkel cells of the skin. K20 expression is used as a marker to distinguish metastatic tumor origin, but nothing is known regarding its regulation and function. We studied K20 phosphorylation as a first step toward understanding its physiologic role. K20 phosphorylation occurs preferentially on serine, with a high stoichiometry as compared with keratin polypeptides 18 and 19. Mass spectrometry analysis predicted that either K20 Ser¹³ or Ser¹⁴ was a likely phosphorylation site, and Ser¹³ was confirmed as the phospho-moiety using mutation and transfection analysis and generation of an anti-K20-phospho-Ser¹³ antibody. K20 Ser¹³ phosphorylation increases after protein kinase C activation, and Ser¹³-to-Ala mutation interferes with keratin filament reorganization in transfected cells. In physiological contexts, K20 degradation and associated Ser¹³ hyperphosphorylation occur during apoptosis, and chemically induced mouse colitis also promotes Ser¹³ phosphorylation. Among mouse small intestinal enterocytes, K20 Ser¹³ is pref erentially phosphorylated in goblet cells and undergoes dramatic hyperphosphorylation after starvation and mucin secretion. Therefore, K20 Ser¹³ is a highly dynamic protein kinase C-related phosphorylation site that is induced during apoptosis and tissue injury. K20 Ser¹³ phosphorylation also serves as a unique marker of small intestinal goblet cells.

Received for publication, November 16, 2005 , and in revised form, April 10, 2006.

^* This work was supported in part by National Institutes of Health (NIH) Grant DK52951 and Department of Veterans Affairs Merit Awards (to M. B. O.), NIH Grant RR 01614 (to A. L. B.), and by NIH Digestive Disease Center Grant DK56339. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Supported by a Veterans Affairs Research Enhancement Award. To whom reprint requests should be addressed. E-mail: qzhou{at}stanford.edu.

² To whom correspondence should be addressed: Palo Alto Veterans Affairs Medical Center, Mail Code 154J, 3801 Miranda Ave., Palo Alto, CA 94304. Fax: 650-852-3259.

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