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Molecular and Cellular Biology, July 2006, p. 5421-5435, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02437-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Ectodomain Shedding of Preadipocyte Factor 1 (Pref-1) by Tumor Necrosis Factor Alpha Converting Enzyme (TACE) and Inhibition of Adipocyte Differentiation

Yuhui Wang and Hei Sook Sul*

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720

Received 21 December 2005/ Returned for modification 2 February 2006/ Accepted 20 April 2006

Preadipocyte factor 1 (Pref-1), an epidermal growth factor repeat containing transmembrane protein found in the preadipocytes, inhibits adipocyte differentiation in vitro and in vivo. Here, we examined the processing of membrane form of Pref-1A to release the 50-kDa soluble form that inhibits adipocyte differentiation. The ectodomain cleavage of Pref-1 is markedly enhanced by phorbol 12-myristate 13-acetate in a dose- and time-dependent manner. The basal and stimulated cleavage is inhibited by the broad metalloproteinase inhibitor GM6001, a fact that suggests that cleavage of membrane Pref-1A is dependent on a metalloproteinase. Next, we showed that release of soluble Pref-1A is inhibited by TAPI-0 and by a tissue inhibitor of metalloproteinase-3, TIMP-3, that can inhibit tumor necrosis factor alpha converting enzyme (TACE), but not by TIMP-1 or TIMP-2. On the other hand, overexpression of TACE increases Pref-1 cleavage to produce the 50-kDa soluble form. Furthermore, this cleavage was not detected in cells with TACE mutation or with TACE small interfering RNA. TACE-mediated shedding of Pref-1 ectodomain inhibits adipocyte differentiation of 3T3-L1 cells and in Pref-1-null mouse embryo fibroblasts transduced with Pref-1A. Identification of TACE as the major protease responsible for conversion of membrane-bound Pref-1 to the biologically active diffusible form provides a new insight into Pref-1 function in adipocyte differentiation.

* Corresponding author. Mailing address: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720. Phone: (510) 642-3978. Fax: (510) 642-0535. E-mail: hsul{at}nature.berkeley.edu.

Molecular and Cellular Biology, July 2006, p. 5421-5435, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.02437-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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