Evidence that fibulin family members contibute to the steroid-dependent extra-vascular sequestration of sex hormone-binding globulin

doi:10.1074/jbc.M512370200

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Papers In Press, published online ahead of print April 6, 2006
J. Biol. Chem, 10.1074/jbc.M512370200
Submitted on November 17, 2005
Revised on April 6, 2006
Accepted on April 6, 2006

Evidence that fibulin family members contibute to the steroid-dependent extra-vascular sequestration of sex hormone-binding globulin

Kwong-Man Ng, Maria G. Catalano, Tomas Pinos, David M. Selva, George V. Avvakumov, Francina Munell, and Geoffrey L. Hammond

Obstetrics & Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4

Corresponding Author: ghammond{at}cw.bc.ca

Sex hormone-binding globulin (SHBG) binds steroids in the blood but is also present in extra-vascular 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 carboxy-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 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.

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