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Submitted on January 23, 2006
Accepted on April 10, 2006
Reproductive Endocrine Unit, Massachusetts General Hospital, Boston MA 02114
* To whom correspondence should be addressed. E-mail: Schneyer.alan{at}mgh.harvard.edu.
Follistatin (FST) and follistatin like-3 (FSTL3) are activin binding and neutralization proteins that also bind myostatin. Three FST isoforms have been described that differ in tissue distribution and cell-surface binding activity, suggesting that the FST isoforms and FSTL3 may have some non-overlapping biological actions. We produced recombinant FST isoforms and FSTL3 and compared their biochemical and biological properties. Activin binding affinities and kinetics were comparable between the isoforms and FSTL3 while cell surface binding differed markedly (FST288>FST303>FST315>FSTL3). Inhibition of endogenous activin bioactivity, whether the FST isoforms were administered endogenously or exogenously, correlated closely with surface binding activity, whereas neutralization of exogenous activin when FST and FSTL3 were also exogenous was consistent with their equivalent activin binding affinities. This difference in activin inhibition was also evident in an in vitro bioassay since FST288 suppressed, while FST315 enhanced activin-dependent TT cell proliferation. Moreover, when FSTL3, which does not associate with cell membranes, was expressed as a membrane anchored protein, its endogenous activin inhibitory activity was dramatically increased. In competitive binding assays, myostatin was more potent than BMPs 6 and 7, and BMPs 2 and 4 were inactive in binding to FST isoforms while none of the BMPs tested competed with activin for binding to FSTL3. Neutralization of exogenous BMP or myostatin bioactivity correlated with the relative abilities of the isoforms to bind cell surface proteoglycans. These results indicate that the differential biological actions among the FST isoforms and FSTL3 are primarily dependent on their relative cell surface binding ability and ligand specificity.
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