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

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. 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. Biologically active androgens and estrogens are transported in the blood by proteins, including sex hormone-binding globulin (SHBG), 4The abbreviations used are: SHBG, sex hormone-binding globulin; GST, glutathione S-transferase; RT-PCR, reverse transcriptase-PCR. and SHBG concentrations are the main determinant of the plasma distribution of these sex steroids between the protein-bound and non-protein-bound fractions (1Siiteri P.K. Murai J.T. Hammond G.L. Nisker J.A. Raymoure W.J. Kuhn R.W. Recent Prog. Horm. Res. 1982; 38: 457-510PubMed Google Scholar). This is important because only non-protein-bound or “free” steroids diffuse from blood vessels to their target cells, according the “free hormone hypothesis” (2Mendel C.M. Endocr. Rev. 1989; 10: 232-274Crossref PubMed Scopus (788) Google Scholar). However, this process is influenced by physiological and anatomical variables, including blood flow and transit time in a given tissue, the extent of tissue vascularization and vascular permeability, the lipid composition of cell types in various compartments within tissues, and the extracellular matrix composition (2Mendel C.M. Endocr. Rev. 1989; 10: 232-274Crossref PubMed Scopus (788) Google Scholar). These are important considerations because in some organs the free steroid must traverse several cell types within the stroma, such as lipid-rich adipose cells, as well as the complex macromolecular structure of the basal lamina, before gaining access to target epithelial cells. Occupancy of the SHBG steroid-binding site varies depending on physiological state and circulating steroid levels, with almost all sites being unoccupied in children prior to puberty, and substantially greater occupancy of the sites in men than in women (3Hammond G.L. Obstet. Gynecol. Clin. North Am. 2002; 29: 411-423Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). High resolution crystal structure analyses have shown that each subunit of the human SHBG homodimer contains a high affinity binding site for both testosterone and estradiol within its amino-terminal laminin G-like (LG-4) domain (4Westphal U. Steroid-Protein Interactions II. Monographs on Endocrinology. Springer-Verlag, Berlin1986: 276-301Google Scholar, 5Hildebrand C. Bocchinfuso W.P. Dales D. Hammond G.L. Biochemistry. 1995; 34: 3231-3238Crossref PubMed Scopus (34) Google Scholar, 6Avvakumov G.V. Grishkovskaya I. Muller Y.A. Hammond G.L. J. Biol. Chem. 2001; 276: 34453-34457Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar) and that androgens and estrogens are oriented differently within this site (7Grishkovskaya I. Avvakumov G.V. Hammond G.L. Catalano M.G. Muller Y.A. J. Biol. Chem. 2002; 277: 32086-32093Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Moreover, occupancy of the steroid-binding site by different types of steroids influences the conformation of the LG-4 domain (6Avvakumov G.V. Grishkovskaya I. Muller Y.A. Hammond G.L. J. Biol. Chem. 2001; 276: 34453-34457Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar), especially in relation to a flexible loop structure that covers the steroid-binding pocket (8Grishkovskaya I. Avvakumov G.V. Hammond G.L. Muller Y.A. J. Mol. Biol. 2002; 318: 621-626Crossref PubMed Scopus (17) Google Scholar). Interestingly, this region of the LG-4 domain of SHBG represents either a ligand-binding site or a macromolecular interaction domain in several structurally related proteins, such as neurexin, serum amyloid P component, and laminin-2α (9Rudenko G. Hohenester E. Muller Y.A. Trends Biochem. Sci. 2001; 26: 363-368Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Steroid ligand-dependent interactions between plasma SHBG and cell membranes have been reported (10Avvakumov G.V. Zhuk N.I. Strel'chyonok O.A. Biochim. Biophys. Acta. 1986; 881: 489-498Crossref PubMed Scopus (46) Google Scholar, 11Hryb D.J. Khan M.S. Romas N.A. Rosner W. J. Biol. Chem. 1990; 265: 6048-6054Abstract Full Text PDF PubMed Google Scholar, 12Porto C.S. Musto N.A. Bardin C.W. Gunsalus G.L. Endocrinology. 1992; 130: 2931-2936Crossref PubMed Scopus (50) Google Scholar). The current consensus is that unliganded SHBG interacts with a receptor located within the plasma membranes of some steroid-sensitive cell types, including breast (13Fortunati N. Fissore F. Fazzari A. Berta L. Benedusi-Pagliano E. Frairia R. J. Steroid Biochem. Mol. Biol. 1993; 45: 435-444Crossref PubMed Scopus (49) Google Scholar) and prostate cells (14Hryb D.J. Khan M.S. Romas N.A. Rosner W. J. Biol. Chem. 1989; 264: 5378-5383Abstract Full Text PDF PubMed Google Scholar), and that occupancy of the SHBG steroid-binding site propagates an intracellular signaling event (15Rosner W. Endocr. Rev. 1990; 11: 80-91Crossref PubMed Scopus (537) Google Scholar). However, there is also evidence that SHBG interacts with human endometrial plasma membranes in a steroid ligand-specific manner (10Avvakumov G.V. Zhuk N.I. Strel'chyonok O.A. Biochim. Biophys. Acta. 1986; 881: 489-498Crossref PubMed Scopus (46) Google Scholar). Although the identity of plasma membrane “receptors” for SHBG remains obscure, ligands (e.g. protein S and gas-6) for members of the tyro-family of orphan tyrosine kinases receptors comprise a carboxyl-terminal region, which resembles the tandem LG-4/LG-5 domain structure of SHBG and functions as their receptor-binding site (16Mark M.R. Chen J. Hammonds G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). it been reported that binds and an A. R. J. N. J. A. Full Text Full Text PDF PubMed Scopus Google Scholar), as in human breast cells C.S. Gunsalus G.L. Bardin C.W. Musto N.A. Endocrinology. PubMed Scopus (49) Google Scholar) and epithelial cells of the Gunsalus G.L. Musto N.A. Bardin C.W. Endocrinology. PubMed Scopus Google Scholar). of mice that express human SHBG Hammond G.L. Mol. PubMed Scopus Google Scholar), have that human SHBG accumulates in the stroma of several sex steroid-sensitive tissues in which the are not such as the endometrium and and that the of human SHBG from the blood by the endometrial stroma of mice is enhanced by These an active to sex steroid to target tissue the this extravascular of plasma SHBG, to proteins that interact with human SHBG in two-hybrid screens of a human prostate by the LG-4 domain of SHBG as and proteins for their to interact with human SHBG in These revealed that the matrix-associated proteins, fibulin-1D and interact with SHBG in a sex steroid-dependent manner, and of these proteins in the endometrial stroma that members to the ligand-dependent of human SHBG within the extravascular compartments of some sex steroid-sensitive tissues in expressing human SHBG and their wild-type have been Hammond G.L. Mol. PubMed Scopus Google Scholar). some mice were a Mice were with and and the were by the of the on the of with tissues of or wild-type mice were in by with by in the tissues were in for and as Hammond G.L. Mol. PubMed Scopus Google Scholar). The used for SHBG by G.V. Muller Y.A. Hammond G.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), which also fibulin-1 and fibulin-2 by R. proteins were located the or In mice were by with of of in of for This to in uterine and to that the were the of mice either of or of estradiol or of in the of by mice were the with either of physiological of unliganded human SHBG, or the of human SHBG in the presence of a of either estradiol or blood were for a binding of SHBG concentrations G.L. Clin. Acta. PubMed Scopus Google Scholar), and the mice were for as Yeast from the (LG-4) domains of human and SHBG G.L. Musto N.A. Bardin C.W. PubMed Scopus Google Scholar, Hammond G.L. J. PubMed Scopus Google Scholar) were by for the and sites with the domain of These were used as in assays of a human prostate to the domain in with the and the prostate for the on and and were and for by a in the from were and in to the which were used to with In this the proteins were as interacting with both human and SHBG protein and only the human SHBG interactions with and fibulin-2 and the carboxyl-terminal domain of fibulin-1D as a interacting The of interaction between human fibulin-1D and fibulin-2 and SHBG this for the LG-4 domains of and SHBG, the domain of human SHBG and the amino-terminal domain of protein S were by and for the with either the human fibulin-1D or fibulin-2 in the two-hybrid The interaction by both and as the region of human fibulin-2 that interacts with SHBG, of fibulin-2 were by were between the and sites of and the with a of the human SHBG LG-4 and two-hybrid interactions were by of fibulin-1D and of fibulin-2 were from the from the human prostate by and These were the sites of a for E. and the and of proteins, as by protein or the of on and with serum human SHBG in the presence or of sex steroid or or with a from cells that a of human SHBG or human SHBG in the presence of estradiol W.P. Hammond G.L. Mol. PubMed Scopus Google Scholar). were in and serum were by and the were with the serum bound to the were by in by and by a membrane for of human SHBG, as W.P. Hammond G.L. Mol. PubMed Scopus Google Scholar). protein from of human SHBG mice or were and by in The protein of and were with to the fibulin-1 or fibulin-2 were and the were for to to by the protein were by the proteins were and the were with the were in and the protein were and by by for the target proteins. were from of of tissues from and mice an human SHBG transgene. Human SHBG and fibulin-1D and fibulin-2 were by and were in a with for the also from each as a control for and for the used in the SHBG SHBG fibulin-1D fibulin-1D fibulin-2 fibulin-2 in a are reported as of for all between were by by the Human SHBG within the of the and of analyses of tissues from several of mice that express human SHBG Hammond G.L. Mol. PubMed Scopus Google Scholar) revealed of human SHBG in the stroma of the endometrium and This remarkable because that these tissues human SHBG high the human SHBG in the endometrial and stroma to with matrix and In of a that is on the of endometrial epithelial cells A. R. J. N. J. A. Full Text Full Text PDF PubMed Scopus Google Scholar), it is also of to there human SHBG in this of Human SHBG from by the human SHBG are in the of an to the human SHBG within the endometrial stroma from the blood. administered human SHBG the of wild-type mice in the presence or of testosterone or the were and for The serum concentrations of human SHBG in these the time of were which is to that in the blood of mice that express human SHBG Hammond G.L. Endocrinology. PubMed Scopus Google Scholar) and is as high as in the blood of women (1Siiteri P.K. Murai J.T. Hammond G.L. Nisker J.A. Raymoure W.J. Kuhn R.W. Recent Prog. Horm. Res. 1982; 38: 457-510PubMed Google Scholar) or women G.L. M.S. L. Full Text PDF PubMed Google Scholar). human SHBG in the of control Although of human SHBG are present in the of with the protein in the steroid ligands or the presence of of human SHBG were in mice in which the protein administered in the presence of estradiol Moreover, the human SHBG in the stromal matrix and the basal of the endometrial in the with SHBG in with estradiol The of and with the LG-4 of SHBG in a Yeast the in two-hybrid the with that the LG-4 domains of human or SHBG. Although several proteins were in a of two-hybrid screens that human SHBG is sequestered within the stromal matrix of the endometrium and on the matrix-associated proteins, fibulin-1D and which were both as of the LG-4 domain of SHBG In both only the carboxyl-terminal of fibulin-1D and fibulin-2 were present in the from the human prostate the of these the of these fibulin-1D and fibulin-2 to interact with the LG-4 domains of SHBG from several as well as several domain the LG-4 domain within human protein S and the carboxyl-terminal domain of human in two-hybrid The that these fibulin-1D and fibulin-2 interact only with the LG-4 domains of and The region of fibulin-2 as interacting with SHBG is than the fibulin-1D and only within the carboxyl-terminal Moreover, and carboxyl-terminal of this fibulin-2 were in a two-hybrid a interaction domain within the fibulin-2 Interactions between the of and and Human SHBG used to the interaction between the carboxyl-terminal domains of fibulin-1D or fibulin-2 and human SHBG and to the of steroid ligands on these of SHBG for these used serum human SHBG as a of the of the interactions in a in the presence of plasma proteins. The the carboxyl-terminal domains of these members interact with human SHBG and that this is in the presence of with estradiol a interaction than the of from Human SHBG to with and plasma SHBG as of by the of sites W.P. Hammond G.L. Mol. PubMed Scopus Google Scholar), the of SHBG sites to interact with the carboxyl-terminal of fibulin-1D or fibulin-2 to in This that of either of the consensus sites for within human SHBG its to interact with fibulin-1D and fibulin-2 in the presence of and of both sites enhanced these interactions as with human SHBG and of Human SHBG Mice Human SHBG but and used to the of human SHBG in the and from mice expressing an human SHBG transgene and to the of fibulin-1D and fibulin-2 in the and as with tissues. from Hammond G.L. Mol. PubMed Scopus Google Scholar), human SHBG is to the and of both and with only in the In addition, the a of human SHBG transgene in the and and to that the presence of human SHBG in these tissues is because of the of SHBG from the blood. fibulin-1D and fibulin-2 are present in all the and tissues but to most in the and Human SHBG and and within the of Human SHBG and Human SHBG This the interactions between SHBG and fibulin-1D and fibulin-2 in the tissue distribution of human SHBG and fibulin-1 and fibulin-2 in of a human SHBG This that human SHBG fibulin-1 and fibulin-2 are to the endometrial stroma of the with in the cell types or the of the the endometrial stroma, of all proteins the and human SHBG and fibulin-1 to concentrate in the of the basal of the high and fibulin-2 the endometrial stroma the of human SHBG in the endometrial stroma may physiological mice expressing a human SHBG transgene were of the and as by of J. Biol. 2002; PubMed Scopus Google Scholar). The from each of the were by in and for with an for human SHBG, as The were in all and that human SHBG is most in the endometrial stroma proestrus the time plasma estradiol are their Endocrinology. 1992; PubMed Scopus Google Scholar). also the and tissue distribution of fibulin-1D and fibulin-2 in these proteins were present in the endometrial stroma all of the but their and distribution within the depending on The distribution of human SHBG and fibulin-1D and fibulin-2 also in the of an human SHBG this of steroid the uterine stroma substantially of matrix and and human SHBG to the blood vessels that SHBG interacts with fibulin-1 and fibulin-2 within the endometrial stroma, a of assays uterine from human SHBG mice SHBG most in the stromal and SHBG to blood were with SHBG were to the of fibulin-1 or fibulin-2 not This not because of the SHBG in these from the blood vessels by the of human SHBG in a uterine in and SHBG therefore in the Although of human SHBG were present in the uterine and from the blood it only of and there of SHBG fibulin-1 or fibulin-2 were used to these proteins from the proestrus and and and human SHBG W.P. Hammond G.L. Endocrinology. 1992; PubMed Scopus (50) Google Scholar) with both of these The of such as from blood vessels to target cells within tissues been The free hormone may plasma proteins the of steroids that diffuse cells in with such as vascular cells or but it to for the complex that steroids must from blood to target cells in tissues, such as the and have been of SHBG in the extravascular compartments of sex steroid-sensitive tissues G. F. PubMed Scopus Google Scholar, G. Horm. Res. 1990; PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). Human SHBG have been in these tissues by D.J. J. Romas N.A. Rosner W. J. Biol. Chem. 2002; Full Text Full Text PDF Scopus Google Scholar, R. J. J. PubMed Scopus Google Scholar) but have been shown to comprise the for the SHBG This is important because human SHBG are and this in a of for the for of SHBG or that D.J. J. Romas N.A. Rosner W. J. Biol. Chem. 2002; Full Text Full Text PDF Scopus Google Scholar). with in the of SHBG for on human tissues, these have of the extravascular of SHBG in human tissues to or these have used a in which the of human SHBG been well Hammond G.L. Mol. PubMed Scopus Google Scholar, Hammond G.L. Endocrinology. PubMed Scopus Google Scholar) and in which of human SHBG within the stroma of tissues and in which the transgene is not In these their is not in the liver and the only SHBG in their blood is from the human SHBG transgene Hammond G.L. Endocrinology. PubMed Scopus Google Scholar). and important of this is that of wild-type mice us to the of the used to human SHBG in the tissues. The of human SHBG in the and endometrial stroma of mice that it must from the blood. to this in and used wild-type mice for this because SHBG in the and their tissues are by SHBG to the because the well within and endometrial compartments a of the of SHBG interactions within an extravascular also important that the were with estradiol for several to in uterine The of this of are to uterine blood vascular permeability, and but this is by an in cell and which within the endometrial compartments of all In this it is important to that were in the or of the from with on the of human SHBG as with the from that either steroid or testosterone prior to human SHBG the of human SHBG within the endometrial stroma, the different on the of plasma steroid-binding protein within the which a of distribution with for the endometrial stroma us to that SHBG rapidly and from blood to the endometrial stroma where it binds to a of the SHBG to the stromal most with The two-hybrid to SHBG interacting proteins that the LG-4 domain of human SHBG contains the steroid-binding site I. Avvakumov G.V. G. Dales D. Hammond G.L. Muller Y.A. J. PubMed Scopus Google Scholar). reported by J. Steroid Biochem. Mol. Biol. PubMed Scopus Google Scholar), this of numerous SHBG interacting proteins M.G. Hammond G.L. on Google Scholar), but the is to these interactions in and that are SHBG to within the stromal matrix of the and on a of extracellular protein as interacting and these the carboxyl-terminal of fibulin-1D and fibulin-2 the most two-hybrid Moreover, the that two-hybrid interactions between the members and the LG-4 domains of SHBG from several but not with the domain of protein S or the domain of SHBG, us with a that were This by that these interactions were not only in an in but were enhanced by these a that these macromolecular interactions are that the site on SHBG is located within its LG-4 domain and that are differently in the presence of androgens such as the flexible loop located the steroid-binding site (7Grishkovskaya I. Avvakumov G.V. Hammond G.L. Catalano M.G. Muller Y.A. J. Biol. Chem. 2002; 277: 32086-32093Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, I. Avvakumov G.V. Hammond G.L. Muller Y.A. J. Mol. Biol. 2002; 318: 621-626Crossref PubMed Scopus (17) Google Scholar). the carboxyl-terminal of fibulin-1D and fibulin-2 both to the SHBG domain in two-hybrid were that the of sites within the domain of SHBG enhanced its to interact with the carboxyl-terminal of fibulin-1D and fibulin-2 in the Although it is that of N-glycosylation sites on the of SHBG, which effective interactions with the carboxyl-terminal domains of fibulin-1D and it is also that N-glycosylation of SHBG the sites within the LG-4 domain of SHBG. the is it of because SHBG W.P. Hammond G.L. Endocrinology. 1992; PubMed Scopus (50) Google Scholar, G.L. Bocchinfuso W.P. J. Steroid Biochem. Mol. Biol. 1995; PubMed Scopus Google Scholar) may therefore within target tissues an enhanced interaction with matrix-associated proteins in members of the of extracellular matrix-associated proteins, fibulin-1D and fibulin-2 a PubMed Scopus Google Scholar). binding sites for numerous matrix-associated proteins and membrane proteins and as within R. G. Rev. Mol. Biol. PubMed Scopus Google Scholar). in in several of human of which and fibulin-1D have carboxyl-terminal domains that with domain of fibulin-2 R. G. Rev. Mol. Biol. PubMed Scopus Google Scholar). that the ligand-dependent interaction between SHBG and fibulin-2 only a of within domain it is that within this region of these are for with SHBG. and have domain with within the region of fibulin-2 that have as the site R. G. Rev. Mol. Biol. PubMed Scopus Google Scholar). Although their presence within the endometrium remains to several have that are located in the of cells R. G. Rev. Mol. Biol. PubMed Scopus Google Scholar). these also SHBG, also in the of SHBG from the blood and for the of SHBG blood vessels in the endometrial stroma The matrix-associated proteins and fibulin-1D or fibulin-2 were as SHBG interacting proteins for several are both in these tissues, within the extracellular matrix R. G. Rev. Mol. Biol. PubMed Scopus Google Scholar), and with human SHBG within the endometrial stroma of Interactions between fibulin-1D or fibulin-2 and SHBG within the endometrium were also of because are both by in human and endometrial stromal cells A. PubMed Scopus Google Scholar, Gynecol. PubMed Scopus Google Scholar, Mol. PubMed Scopus Google Scholar), and fibulin-1D in the human endometrium in a manner Mol. PubMed Scopus Google Scholar). therefore to these members with human SHBG within the endometrial stroma of and that this most with to the presence of fibulin-1 and SHBG the basal of the epithelial cells. This to us that members may not only to the steroid-dependent of SHBG in the endometrial stroma but may also the of SHBG within different of the stroma. this is interactions a for the of from the blood the stroma to epithelial cells. Although have used a to human SHBG tissues such as the that human SHBG accumulates high in the endometrial stroma of these mice that this may and that may is also important to that this a time plasma estradiol are their Endocrinology. 1992; PubMed Scopus Google Scholar) and that this of the there is an of stromal matrix that is in fibulins and of protein from a human SHBG with or in the of human SHBG. Interestingly, the human SHBG in the is in W.P. Hammond G.L. Endocrinology. 1992; PubMed Scopus (50) Google Scholar), and this the that the binding of SHBG to fibulin-1D or fibulin-2 their extravascular by these matrix-associated proteins. therefore that estradiol the of SHBG from the blood its in the endometrial stroma, and that this is by the binding of SHBG in complex with estradiol to The basal represents an important between the stroma and where are and between these tissue and an of SHBG this site have that of the access of sex steroids to their target epithelial cells. In this matrix-associated proteins a for signaling such as the and an for the of between cell types by the basal J. Biol. 1993; PubMed Scopus Google Scholar, Biol. 10: PubMed Scopus Google Scholar, Biol. 10: Scopus Google Scholar). is also a of between the of estrogens and various and signaling in the extracellular matrix Endocr. PubMed Scopus Google Scholar, Endocrinology. PubMed Scopus Google Scholar). in to the access of steroids to cell types within complex tissues, ligand-dependent interactions between SHBG and matrix-associated proteins, such as fibulin-1 and their binding to various signaling including for the receptor R. Res. 1995; PubMed Scopus Google Scholar), either or of the basal In that interactions between SHBG and members to the extravascular and distribution of SHBG within the stroma of a sex steroid-sensitive This the of plasma SHBG from of and the plasma distribution of its sex steroid ligands and it in a in which it a in the access of steroids to their target cells in tissues. In this the of these with in the of proteins within different tissues different physiological for of that the of sex steroids within tissue compartments and their access to target cells. In addition, given the complex interplay between various matrix-associated proteins, interactions between SHBG and various members that the extracellular matrix and a novel of steroid hormone

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