Follistatin: A Multifunctional Regulatory Protein

Phillips, David J.; Kretser, David Morritz de

doi:10.1006/frne.1998.0169

Cited by 250 publications

(164 citation statements)

References 220 publications

Supporting

Mentioning

158

Contrasting

Unclassified

Order By: Relevance

“…Follistatin has been implicated in the female reproductive axis, pregnancy (reviewed by Phillips & de Kretser 1998) and embryonic development (Tashiro et al 1991, Mummery & van den Eijnden-van Raaij 1993, Tuuri et al 1994. The reported concentrations of total follistatin through pregnancy have been somewhat inconsistent between assays and groups.…”

Section: Introductionmentioning

confidence: 99%

Follistatin serum concentrations during full-term labour in women – significant differences between spontaneous and induced labour

Rae

Hollebone²,

Chetty³

et al. 2007

Reproduction

View full text Add to dashboard Cite

Follistatin has been isolated from human placenta and has been identified in human foetal membranes and fluids. Serum follistatin levels in women rise during pregnancy particularly near term. In this study, we examined the effect of induction and stage of labour on maternal plasma concentrations of follistatin. Women who gave birth after a normal pregnancy were retrospectively divided into three groups: those who went in labour spontaneously (nZ33), needed induction by amniotomy and IV oxytocin (nZ18) or underwent planned caesarean section (nZ10). Serum was collected at 38-40 weeks of gestation, periodically through labour with a vaginal examination and once within 36 h postpartum and assayed for oestradiol, progesterone, prolactin and C-reactive protein. Follistatin was measured using a rabbit antiserum (#204) raised against purified 35 kDa bovine follistatin. Human recombinant follistatin was used as both standard and tracer. Concentrations of follistatin at 38-40 weeks of gestation were significantly different between groups. Those who had a spontaneous labour had concentrations higher than those who were induced. Similarly, those who were induced had concentrations higher than those who underwent a caesarean. In the spontaneous group, follistatin rose during labour, peaking at 57.9G5.48 ng/ml at O3 cm of cervical dilation, and after delivery follistatin decreased to 26.16G3.4 ng/ml at 24 h post-delivery. In induced patients follistatin continued increasing to peak following delivery at 26.9G3.0 ng/ml and decreased at O3 h post-delivery. Follistatin concentrations in caesarean section patients at 24 h post-surgery (18.53G3.74 ng/ml) were not different from that before the surgery and were comparable with the other two groups. Follistatin is clearly implicated in the onset of labour; however, further studies with a larger cohort of women are necessary to determine the nature of its role. Reproduction (2007) 134 705-711

show abstract

Section: Introductionmentioning

confidence: 99%

Follistatin serum concentrations during full-term labour in women – significant differences between spontaneous and induced labour

Rae

Hollebone²,

Chetty³

et al. 2007

Reproduction

View full text Add to dashboard Cite

show abstract

“…Follistatin is composed of an N-terminal domain (ND), and three follistatin domains (FSD1-3; see Fig. 1A), each of which is further divided into epidermal growth factor-like and a kazal protease inhibitor-like sub-domains (28). FSD1, FSD2, and FSD3 adopt different internal arrangements of the two subdomains, which appear to act as separately folded units with structural but not functional linkage to epidermal growth factor ligands or protease inhibitors.…”

mentioning

confidence: 99%

Structural and Biophysical Coupling of Heparin and Activin Binding to Follistatin Isoform Functions

Lerch

Shimasaki

Woodruff

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Follistatin (FS) regulates transforming growth factor-␤ superfamily ligands and is necessary for normal embryonic and ovarian follicle development. Follistatin is expressed as two splice variants (FS288 and FS315). Previous studies indicated differences in heparin binding between FS288 and FS315, potentially influencing the physiological functions and locations of these isoforms. We have determined the structure of the FS315-activin A complex and quantitatively compared heparin binding by the two isoforms. The FS315 complex structure shows that both isoforms inhibit activin similarly, but FS315 exhibits movements within follistatin domain 3 (FSD3) apparently linked to binding of the C-terminal extension. Surprisingly, the binding affinities of FS288 and FS315 for heparin are similar at lower ionic strengths with FS315 binding decreasing more sharply as a function of salt concentration. When bound to activin, FS315 binds heparin similarly to the FS288 isoform, consistent with the structure of the complex, in which the acidic residues of the C-terminal extension cannot interact with the heparin-binding site. Activin-induced binding of heparin is unique to the FS315 isoform and may stimulate clearance of FS315 complexes.Ligands of the transforming growth factor-␤ (TGF␤) 3 superfamily regulate a diverse set of cellular and physiological functions, including early embryonic development, cellular growth and proliferation, and reproduction (1-3). Activin A, a member of the TGF␤ superfamily, is necessary to the regulation of both the male and the female reproductive axes by stimulating the release of follicle-stimulating hormone from the pituitary (4, 5). Activin A also has other important physiological roles, because activin A-deficient mice die shortly after birth and exhibit multiple defects in craniofacial development (6, 7). Comparative studies of the similarities and differences between TGF␤ ligands have lead to a better understanding of the many physiological effects of this multipotent ligand superfamily.TGF␤ superfamily members typically exist as covalently linked dimers and fall into three main sub-categories: TGF␤s, activins/inhibins/nodals, and bone morphogenetic proteins (BMPs) (8). Structurally, these proteins all share a cysteine-knot fold and signal by engaging type II and type I receptors (9). Activin and BMPs bind to their type II receptors through a structural feature known as the "knuckle" region (10 -12). They have similar type I receptor binding sites on the concave surfaces of the molecule, which span both monomers of the ligands (13-16). Although specific ligand:receptor pairs have been characterized, multiple ligands share several receptors providing complexity and precise control to the system. The members of this superfamily are produced as prepro-proteins, and the pro-domain often regulates biological functions. In the absence of the pro-domain, TGF␤-1 and -2, as well as BMP-2, -4, and -7, can bind directly to the cell surface through heparin binding sites (17,18). This provides a mechanism f...

show abstract

“…The secreted polypeptide follistatin regulates several signaling pathways in a cell-and tissue-specific manner, largely through its ability to inactivate transforming growth factor-␤-like growth factor molecules (1,2). Although first identified as a factor capable of countering the inducing effects of activin on follicle-stimulating hormone secretion (3,4), follistatin has now been isolated and characterized from a variety of tissues and organisms, where it has been shown to take part in processes such as cell growth, differentiation, and secretion (5-7).…”

mentioning

confidence: 99%

Crystal Structures of the Heparan Sulfate-binding Domain of Follistatin

Innis

Hyvönen

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Follistatin associates with transforming growth factor-␤-like growth factors such as activin or bone morphogenetic proteins to form an inactive complex, thereby regulating processes as diverse as embryonic development and cell secretion. Although an interaction between heparan sulfate chains present at the cell surface and follistatin has been recorded, the impact of this binding reaction on the follistatin-mediated inhibition of transforming growth factor-␤-like signaling remains unclear. To gain a structural insight into this interaction, we have solved the crystal structure of the presumed heparan sulfate-binding domain of follistatin, both alone and in complex with the small heparin analogs sucrose octasulfate and D-myo-inositol hexasulfate. In addition, we have confirmed the binding of the sucrose octasulfate and D-myo-inositol hexasulfate molecules to this follistatin domain and determined the association constants and stoichiometries of both interactions in solution using isothermal titration calorimetry. Overall, our results shed light upon the structure of this follistatin domain and reveal a novel conformation for a hinge region connecting epidermal growth factor-like and Kazal-like subdomains compared with the follistatin-like domain found in the extracellular matrix protein BM-40. Moreover, the crystallographic analysis of the two protein-ligand complexes mentioned above leads us to propose a potential location for the heparan sulfate-binding site on the surface of follistatin and to suggest the involvement of residues Asn 80 and Arg 86 in such a follistatin-heparin interaction.The secreted polypeptide follistatin regulates several signaling pathways in a cell-and tissue-specific manner, largely through its ability to inactivate transforming growth factor-␤-like growth factor molecules (1, 2). Although first identified as a factor capable of countering the inducing effects of activin on follicle-stimulating hormone secretion (3, 4), follistatin has now been isolated and characterized from a variety of tissues and organisms, where it has been shown to take part in processes such as cell growth, differentiation, and secretion (5-7). Moreover, the importance of this polypeptide has been demonstrated in follistatin-null mice, which can survive birth but die from multiple skeletal and cutaneous abnormalities within a few hours of delivery (8).Follistatin isoforms sharing the same N terminus but differing in the length of their polypeptide chain and in their glycosylation patterns coexist in vivo, with molecular masses ranging from 31 to 39 kDa (4, 9). Indeed, alternative splicing of the follistatin gene yields the Fs-315 and Fs-288 isoforms, featuring 315 and 288 residues, respectively. An additional variant of follistatin, Fs-303, is thought to arise from the proteolytic cleavage of the Fs-315 C terminus and is likely to be the predominant species in vivo (3, 10, 11). Despite its relatively limited size, follistatin contains a total of 36 cysteine residues, believed to be arranged into nonoverlapping set...

show abstract

Follistatin: A Multifunctional Regulatory Protein

Cited by 250 publications

References 220 publications

Follistatin serum concentrations during full-term labour in women – significant differences between spontaneous and induced labour

Follistatin serum concentrations during full-term labour in women – significant differences between spontaneous and induced labour

Structural and Biophysical Coupling of Heparin and Activin Binding to Follistatin Isoform Functions

Crystal Structures of the Heparan Sulfate-binding Domain of Follistatin

Contact Info

Product

Resources

About