Human follistatin-related protein: A structural homologue of follistatin with nuclear localization

Follistatin-related protein is a recently discovered glycoprotein that is h ighly homologous in both primary sequence and exon/intron domain structure to the activin-binding protein, follistatin. We explored their potential fo r functional redundancy by investigating the relative affinities and kineti cs of their interactions with activin, bone morphogenic protein-6, and bone morphogenic protein-7 and by exploring their expression and distribution i n human tissues and cells. Follistatin and follistatin-related protein mRNA were ubiquitous by Northern analyses, although their sites of peak distrib ution differed, with follistatin-related protein and follistatin predominat ing in the placenta and ovary, respectively. Follistatin-related protein, l ike follistatin, preferentially bound activin with high affinity and in an essentially irreversible fashion. Although follistatin-related protein, lik e follistatin, possesses a signal sequence and no known nuclear localizatio n signals, its secretion was undetectable in most cell lines by RIA. Intrig uingly, follistatin-related protein was identified as a nuclear protein in human granulosa cells and all human cell lines tested. Furthermore, Western analyses of CHO cells transfected with human follistatin-related protein r evealed this protein to reside within the insoluble nuclear protein fractio n. We conclude that despite its remarkably high level of similarity to foll istatin with regard to structure and activin binding kinetics, follistatin- related protein is a nuclear as well as a secretory protein that may perfor m distinct intracellular actions.