Secretion of FGF-16 Requires an Uncleaved Bipartite Signal Sequence

Miyakawa, Kazuko; Imamura, Toru

doi:10.1074/jbc.m300690200

Cited by 37 publications

(34 citation statements)

References 38 publications

(34 reference statements)

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“…FGF9, FGF16, and FGF20 do not have a classical signal sequence. They are efficiently secreted in an ER/Golgi-dependent pathway because of the presence of a high hydrophobic N-terminal region and a six amino acid-long region located within the core (22)(23)(24). We have shown here that LET-756, which like FGF9, FGF16, and FGF20 does not have a typical N-terminal signal sequence, is efficiently secreted by a Golgi-associated mechanism depend- FIG.…”

Section: Let-756 Resembles Fgf9mentioning

confidence: 86%

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Functional Phylogeny Relates LET-756 to Fibroblast Growth Factor 9

Popovici

Conchonaud

Birnbaum

et al. 2004

Journal of Biological Chemistry

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Fibroblast growth factors (FGFs) are secreted regulatory proteins involved in various developmental processes. In vertebrates, the FGF superfamily comprises 22 members. In non-vertebrates, six FGF genes have been identified in Ciona intestinalis, three in Drosophila melanogaster, and two (let-756 and egl-17) in Caenorhabditis elegans. The core of LET-756 shares a 30 -50% sequence identity with the various members of the superfamily. The relationships between vertebrate and non-vertebrate FGFs are not clear. We made chimeric FGFs by replacing the core region of LET-756 by the cores of various mammalian, fly, and worm FGFs. LET-756 deleted in its core region was no longer able to rescue the lethal phenotype of a let-756 null mutant, and only chimeras containing the cores of FGFs 9, 16, and 20 showed rescue capacity. This core contains an internal motif of six amino acid residues (EFISIA) whose deletion or mutation abolished both the rescue activity and FGF secretion in the supernatant of transfected COS-1 cells. Chimera containing the core of C. intestinalis FGF9/16/ 20, a potential ortholog of FGF9 lacking the complete EFISIA motif, was not able to rescue the lethal phenotype or be secreted. However, the introduction of the EFISIA motif restored both activities. The data show that the EFISIA motif in the core of LET-756 is essential for its biological activity and that FGFs 9, 16, and 20, which contain that motif, are functionally close to LET-756 and may be evolutionary related. This non-classical mode of secretion using an internal motif is conserved throughout evolution. Fibroblast growth factors (FGF)1 are secreted regulatory proteins. In vertebrates, the FGF superfamily comprises 22 members involved in various developmental processes including the formation of mesoderm during gastrulation, patterning during early post-implantation, and development of various tissues such as ear, limb, hair, and nervous and skeletal systems (1). This role has been established through a series of studies on animal models and identification of human hereditary skeletal disorders that are associated with mutations of the tyrosine kinase FGF receptors (2, 3). In non-vertebrates, only a few FGF genes have been identified and characterized. To speak only of fully sequenced genomes, three Fgf genes are known in Drosophila melanogaster (4, 5), two in Caenorhabditis elegans (let-756 and egl-17) (6, 7), and six in the small marine ascidian Ciona intestinalis (8, 9). 2Phylogenetic analysis allows classification of FGFs in several families that separated early during the evolution of bilaterians (8, 10 -12). In the human genome, the FGF families are included into distinct sets of paralogous chromosomal regions (13). This classification is associated with the structural and functional properties of FGFs. For example, the FGF homologous factors (FHF), which in contrast to all other FGFs, exert their function by ways independent of the FGF receptors (14, 15) group in a separate family. However, this analysis is not conclusive for the non-ve...

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Section: Let-756 Resembles Fgf9mentioning

confidence: 86%

“…For example, LET-756 shares nuclear localization with FGF1, FGF2, FGF3, and FHFs (for review see Ref. 24) and muscle expression with FGF5, FGF6, and FGF9 (24 -26). From an evolutionary point of view, two striking features are associated with the FGF superfamily.…”

Section: Discussionmentioning

confidence: 99%

Functional Phylogeny Relates LET-756 to Fibroblast Growth Factor 9

Popovici

Conchonaud

Birnbaum

et al. 2004

Journal of Biological Chemistry

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“…Therefore, the signal peptidase does not recognize a specific sequence in the cleavage site, and not every transmembrane or secreted protein is necessarily cleaved by signal peptidase (e.g. fibroblast growth factor (FGF)-9 and FGF-16 (33,34)). The molecular weights of membrane-bound DR5 and nuclear DR5 were similar in our Western blot analysis, suggesting that the signal peptide sequence in DR5 is not targeted by a signal peptidase.…”

Section: Discussionmentioning

confidence: 99%

Importin β1 Protein-mediated Nuclear Localization of Death Receptor 5 (DR5) Limits DR5/Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Cell Death of Human Tumor Cells

Kojima

Nakayama

Nishina

et al. 2011

Journal of Biological Chemistry

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Background: Nuclear localization of DR5 was observed in TRAIL-resistant tumor cells in human. Results: TRAIL-resistant tumor cells were sensitized to TRAIL by knockdown of importin ␤1. Conclusion: Importin ␤1-mediated nuclear translocation of DR5 limits DR5/TRAIL-induced cell death of human tumor cells.Significance: This provides a novel strategy to improve the efficiency of recombinant TRAIL and anti-DR5 antibodies in cancer therapy.

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“…Interestingly, the mutated synthetic signal peptide functioned as an efficient signal peptide, even though the secreted protein found in hemolymph had an intact signal peptide at its N-terminus. The S-sp m -PsLH with a non-functional signal peptide would be secreted through the ER and Golgi apparatus, since several proteins lacking a cleavable signal sequence, such as fibroblast growth factors (FGFs)-9 and -16, have been reported to be secreted by the conventional pathway [23,24].…”

Section: Efficiency Of Recombinant Protein Secretion Directed By Eachmentioning

confidence: 99%

Comparison of signal peptides for efficient protein secretion in the baculovirus-silkworm system

et al. 2013

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The baculovirus-silkworm expression system is widely used as a mass production system for recombinant secretory proteins. However, the final yields of some recombinant proteins are not sufficient for industrial use. In this study, we focused on the signal peptide as a key factor for improving the efficiency of protein production. Endoplasmic reticulum (ER) translocation of newly synthesized proteins is the first stage of the secretion pathway; therefore, the selection of an efficient signal peptide would lead to the efficient secretion of recombinant proteins. The Drosophila Bip and honeybee melittin signal peptides have often been used in this system, but to the best of our knowledge, there has been no study comparing secretion efficiency between exogenous and endogenous signal peptides. In this study we employed signal peptides from 30K Da and SP2 proteins as endogenous signals, and compared secretion efficiency with those of exogenous or synthetic origins. We have found that the endogenous secretory signal from the 30K Da protein is the most efficient for recombinant secretory protein production in the baculovirus-silkworm expression system.

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Secretion of FGF-16 Requires an Uncleaved Bipartite Signal Sequence

Abstract: Fibroblast growth factor (FGF)-

Cited by 37 publications

References 38 publications

Functional Phylogeny Relates LET-756 to Fibroblast Growth Factor 9

Functional Phylogeny Relates LET-756 to Fibroblast Growth Factor 9

Importin β1 Protein-mediated Nuclear Localization of Death Receptor 5 (DR5) Limits DR5/Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Cell Death of Human Tumor Cells

Comparison of signal peptides for efficient protein secretion in the baculovirus-silkworm system

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