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Volume 272, Number 21, Issue of May 23, 1997 pp. 13835-13842
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

A Novel Role of Follistatin, an Activin-binding Protein, in the Inhibition of Activin Action in Rat Pituitary Cells
ENDOCYTOTIC DEGRADATION OF ACTIVIN AND ITS ACCELERATION BY FOLLISTATIN ASSOCIATED WITH CELL-SURFACE HEPARAN SULFATE

(Received for publication, September 18, 1996, and in revised form, December 30, 1996)

Osamu Hashimoto ^§ , Takanori Nakamura , Hiroki Shoji , Shunichi Shimasaki ^¶ , Yoshihiro Hayashi ^§ and Hiromu Sugino

From the  Institute for Enzyme Research, University of Tokushima, Kuramoto, Tokushima 770, Japan, the ^§ Department of Veterinary Anatomy, Faculty of Agriculture, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113, Japan, and ^¶ Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093-0674

There are two types of the activin-binding protein follistatin (FS), FS-288 and FS-315. These result from alternative splicing of mRNA. FS-288 exhibits high affinity for cell-surface heparan sulfate proteoglycans, whereas FS-315 shows low affinity. To understand the physiological role of cell-associated FS, we investigated the binding of activin to cell-associated FS and its behavior on the cell surface using primary cultured rat pituitary cells. Affinity cross-linking experiments using ¹²⁵I-activin A demonstrated that activin bound to rat pituitary cells via FS as well as to their receptors on the cell surface. FS-288 promoted the binding of activin A to the cell surface more markedly than FS-315. When the cells were incubated with ¹²⁵I-activin A in the presence of FS-288, significant degradation of activin A was observed, and this was dependent on the FS-288 concentration. This activin degradation was abolished by heparan sulfate, chloroquine, and several lysosomal enzyme inhibitors. Moreover, FS-288 stimulated cellular uptake of activin A, whereas chloroquine suppressed lysosomal degradation following internalization, as demonstrated by microscopic autoradiography. These results suggest that cell-associated FS-288 accelerates the uptake of activin A into pituitary cells, leading to increased degradation by lysosomal enzymes, and thus plays a role in the activin clearance system.

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