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J Biol Chem, Vol. 274, Issue 41, 29352-29357, October 8, 1999

A Hydrophobic Region Locating at the Center of Fibroblast Growth Factor-9 Is Crucial for Its Secretion

Kazuko Miyakawa^§, Kiyotaka Hatsuzawa, Tsutomu Kurokawa^**, Masahiro Asada, Tomoko Kuroiwa, and Toru Imamura

From the  Biosignaling Department, National Institute of Bioscience and Human Technology, Tsukuba, Ibaraki 305-8566, the ^§ Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8577, the  School of Life Science, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachijyoji, Tokyo 192-0392, and ^** Discovery Research Laboratories 1, Takeda Chemical Industries Company, Ltd., Tsukuba, Ibaraki 300-4293, Japan

Fibroblast growth factor (FGF)-9 is a glycosylated neurotrophic polypeptide highly expressed in brain. The mechanism for its secretion from expressing cells is unclear, because its primary structure lacks a cleavable signal sequence. We, therefore, investigated the mechanism and structural requirements for secretion of FGF-9. As with other secreted proteins, in vitro translation of FGF-9 was inhibited by signal recognition particle, which binds to the signal sequence. When translated in vitro, full-length FGF-9 was translocated into microsomes, glycosylated, and protected from trypsin digestion. By using various FGF-9 deletion mutants, we found that two hydrophobic domains, located at the N terminus and at the center of the FGF-9 primary structure, were crucial for translocation. Examination of various point mutants revealed that local hydrophobicity of the central hydrophobic domain, but not the N terminus, was crucial for translocation. Analogous results were obtained with respect to FGF-9 secretion from transfectant cells. Upon deletion of the complete sequence preceding it, the previously uncleavable hydrophobic domain appeared to serve as a cleavable signal sequence. Our results suggest that nascent FGF-9 polypeptides translocate into endoplasmic reticulum without peptide cleavage via a co-translational pathway in which both the N terminus and the central hydrophobic domain are important; thereafter, FGF-9 is glycosylated and secreted.

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