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J. Biol. Chem., Vol. 281, Issue 23, 15853-15861, June 9, 2006

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Evidence That Fibulin Family Members Contribute to the Steroid-dependent Extravascular Sequestration of Sex Hormone-binding Globulin^*

Kwong-Man Ng, Maria G. Catalano¹², Tomàs Pinós^¶1, David M. Selva, George V. Avvakumov^||, Francina Munell^¶, and Geoffrey L. Hammond³

From the Department of Obstetrics and Gynecology, University of British Columbia, and Child and Family Research Institute, Vancouver V5Z 4H4, Canada, the Department of Clinical Pathophysiology, University of Turin, Turin 10126, Italy, the ^¶Grup de Recerca Endocrinologia Molecular, Hospital Vall d'Hebron, Barcelona 08035, Spain, and the ^||Structural Genomics Consortium, University of Toronto, Toronto, MSG IL5 Canada

Sex hormone-binding globulin (SHBG) binds steroids in the blood but is also present in the extravascular compartments of some tissues. Mice expressing a human SHBG transgene in the liver have human SHBG in their blood. In these animals, human SHBG accumulates within the stromal matrix of the endometrium and epididymis. This is remarkable because these tissues do not express the transgene. Human SHBG administered intravenously to wild-type mice in the presence of estradiol is rapidly sequestered within the endometrial stroma, and this prompted us to search for SHBG interacting proteins. Yeast two-hybrid screens revealed that fibulin-1D and fibulin-2 interact with the amino-terminal laminin G domain of SHBG. These interactions were verified in GST-pull down assays in which human SHBG bound the carboxyl-terminal domains of fibulin-1D and fibulin-2 in a steroid-dependent manner, with estradiol being the most effective ligand, and were enhanced by reducing the N-glycosylation of human SHBG. Like human SHBG, fibulin-1 and fibulin-2 concentrate within the endometrial stroma. In addition, SHBG co-immunoprecipitates with these fibulins in a proestrus uterine extract. These matrix-associated proteins may therefore sequester plasma SHBG within uterine stroma where it can control sex-steroid access to target cells. Given the interplay between fibulins and numerous proteins within the basal lamina, interactions between SHBG and matrix proteins may exert novel biological effects.

Received for publication, November 17, 2005 , and in revised form, April 6, 2006.

^* This work was supported by grants from the Canadian National Institutes of Health Research (to G. L. H.) and from the Ministerio de Educación y Ciencia and Ministerio de Sanidad y Consumo (to F. M.). 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 Both authors contributed equally to this work.

² Supported by fellowships from Associazione Leonardo Di Capua and Wyeth-Ayerst.

³ Holds the Canada Research Chair in Reproductive Health. To whom correspondence should be addressed: Child and Family Research Institute, 950 West 28th Ave., Vancouver, Canada V5Z 4H4. Tel.: 604-875-2435; Fax: 604-875-2496; E-mail: ghammond{at}cw.bc.ca.

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