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J. Biol. Chem., Vol. 278, Issue 37, 35718-35724, September 12, 2003

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Secretion of FGF-16 Requires an Uncleaved Bipartite Signal Sequence^*

Kazuko Miyakawa   and Toru Imamura  ¶ ||

From the Age Dimension Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8577, and ^¶Institute of Biological Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan

Fibroblast growth factor (FGF)-16 is one of the rare secreted proteins that do not possess a cleavable signal sequence. Here we describe our examination of the mechanism and structural requirements for the secretion of FGF-16 from COS-1 transfectants. Inhibition of its secretion by brefeldin A and identification of an N-glycan on the secreted form confirmed that FGF-16 is secreted by means of the endoplasmic reticulum and Golgi apparatus, as are secreted proteins having a conventional cleavable signal sequence. Deletion of its N terminus abolished secretion of FGF-16. When chimerized with prolactin, however, the N-terminal sequence of FGF-16 was not able to mediate secretion of the chimera. Point mutations that made the N terminus less hydrophobic had little effect on secretion of FGF-16, whereas making the central hydrophobic region less hydrophobic abolished secretion. Within cells, an unsecretable FGF-16 N-terminal deletion mutant was distributed in the perinuclear region and overlapped the distribution of the Golgi apparatus. Mutants with less hydrophobic central regions were distributed evenly throughout the cytosol. Collectively, these results indicate that FGF-16 employs a unique bipartite signal sequence (i.e. both the N-terminal region and central hydrophobic region) that is not cleaved, although it shares the same secretory machinery used by secreted proteins with cleavable signal sequences.

Received for publication, January 21, 2003 , and in revised form, June 9, 2003.

^* This research was supported in part by a Japan Society for the Promotion of Science (JSPS) Research Fellowship for Young Scientist's grant (to K.M.) and by a National Institute of Advanced Industrial Science and Technology (AIST) research grant (to T.I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Age Dimension Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan. Tel.: 81-29-861-2731; Fax: 81-29-861-2792; E-mail: imamura-toru{at}aist.go.jp.

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