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J. Biol. Chem., Vol. 282, Issue 25, 18645-18653, June 22, 2007

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Role of Scarf and Its Binding Target Proteins in Epidermal Calcium Homeostasis^*

Joonsung Hwang, Alexandr Kalinin, Meeyul Hwang, D. Eric Anderson, Min Jung Kim^¶, Olivera Stojadinovic^||, Marjana Tomic-Canic^||, Seung Hun Lee^¶, and Maria I. Morasso¹

From the Developmental Skin Biology Unit, NIAMS, and Proteomics and Mass Spectrometry Facility, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, ^¶Department of Dermatology, Yonsei University College of Medicine, Seoul 135-720, Korea, and ^||Department of Dermatology, Weill Medical College of Cornell University, Hospital for Special Surgery, New York, New York 10021

The novel Ca²⁺-binding protein, Scarf (skin calmodulin-related factor) belongs to the calmodulin-like protein family and is expressed in the differentiated layers of the epidermis. To determine the roles of Scarf during stratification, we set out to identify the binding target proteins by affinity chromatography and subsequent analysis by mass spectrometry. Several binding factors, including 14-3-3s, annexins, calreticulin, ERp72 (endoplasmic reticulum protein 72), and nucleolin, were identified, and their interactions with Scarf were corroborated by co-immunoprecipitation and co-localization analyses. To further understand the functions of Scarf in epidermis in vivo, we altered the epidermal Ca²⁺ gradient by acute barrier disruption. The change in the expression levels of Scarf and its binding target proteins were determined by immunohistochemistry and Western blot analysis. The expression of Scarf, annexins, calreticulin, and ERp72 were up-regulated by Ca²⁺ gradient disruption, whereas the expression of 14-3-3s and nucleolin was reduced. Because annexins, calreticulin, and ERp72 have been implicated in Ca²⁺-induced cellular trafficking, including the secretion of lamellar bodies and Ca²⁺ homeostasis, we propose that the interaction of Scarf with these proteins might be crucial in the process of barrier restoration. On the other hand, down-regulation of 14-3-3s and nucleolin is potentially involved in the process of keratinocyte differentiation and growth inhibition. The calcium-dependent localization and up-regulation of Scarf and its binding target proteins were studied in mouse keratinocytes treated with ionomycin and during the wound-healing process. We found increased expression and nuclear presence of Scarf in the epidermis of the wound edge 4 and 7 days post-wounding, entailing the role of Scarf in barrier restoration. Our results suggest that Scarf plays a critical role as a Ca²⁺ sensor, potentially regulating the function of its binding target proteins in a Ca²⁺-dependent manner in the process of restoration of epidermal Ca²⁺ gradient as well as during epidermal barrier formation.

Received for publication, March 8, 2007 , and in revised form, April 16, 2007.

^* This work was supported by the Intramural Research Program of the NIAMS, National Institutes of Health. 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: Developmental Skin Biology Unit, NIAMS, National Institutes of Health, Bldg. 50, Rm. 1525, Bethesda, MD 20892. Tel.: 301-435-7842; Fax: 301-435-7910; E-mail: morassom{at}mail.nih.gov.

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