Abstract
S100A13, a member of the S100 gene family of Ca(2+)-binding proteins has been previously characterized as a component of a brain-derived heparin-binding multiprotein aggregate/complex containing fibroblast growth factor 1 (FGF1). We report that while expression of S100A13 in NIH 3T3 cells results in the constitutive release of S100A13 into the extracellular compartment at 37 degrees C, co-expression of S100A13 with FGF1 represses the constitutive release of S100A13 and enables NIH 3T3 cells to release S100A13 in response to temperature stress. S100A13 release in response to stress occurs with kinetics similar to that observed for the stress-induced release of FGF1, but S100A13 expression is able to reverse the sensitivity of FGF1 release to inhibitors of transcription and translation. The release of FGF1 and S100A13 in response to heat shock results in the solubility of FGF1 at 100% (w/v) ammonium sulfate saturation, and the expression of a S100A13 deletion mutant lacking its novel basic residue-rich domain acts as a dominant negative effector of FGF1 release in vitro. Surprisingly, the expression of S100A13 also results in the stress-induced release of a Cys-free FGF1 mutant, which is normally not released from NIH 3T3 cells in response to heat shock. These data suggest that S100A13 may be a component of the pathway for the release of the signal peptide-less polypeptide, FGF1, and may involve a role for S100A13 in the formation of a noncovalent FGF1 homodimer.
Highlights
FGF11 and FGF2 are the prototype members of a large family of heparin-binding growth factor genes that regulate numerous biological processes such as neurogenesis, mesoderm formation, and angiogenesis [1, 2]
Because temperature stress of the Myc-S100A13 NIH 3T3 cell transfectants did not alter the heparin affinity of the Myc-S100A13 chimera (Fig. 1B), we suggest that the Myc-S100A13 protein may not be subjected to temperature-mediated post-translational modifications, which may affect its heparin affinity
Like the stress-induced release of fibroblast growth factor 1 (FGF1) [3], p40 Syt1 [7, 8], and murine IL-1␣ [14], the stress-induced release of Myc-S100A13 is sensitive to agents that interfere with ATP biosynthesis and organization of the F-actin cytoskeleton but is insensitive to disruption of intracellular communication between the endoplasmic reticulum (ER)-Golgi apparatus
Summary
FGF11 and FGF2 are the prototype members of a large family of heparin-binding growth factor genes that regulate numerous biological processes such as neurogenesis, mesoderm formation, and angiogenesis [1, 2]. FGF1 and FGF2 lack a classical signal peptide sequence that provides access to the conventional endoplasmic reticulum (ER)-Golgi secretion pathway, a characteristic that led to the hypothesis that the release of these polypeptides may proceed through novel release/export. The release of FGF1 in response to stress is dependent on Syt expression, since the expression of either a deletion mutant lacking 95 amino acids from the extravesicular portion of Syt or an antisense-Syt gene is able to repress FGF1 release in NIH 3T3 cells [7, 8]. We have not been able to eliminate the function of other Syt gene family members in the stress-induced release of IL-1␣, the observation that the precursor form of IL-1␣ is able to block the release of FGF1 in response to temperature stress suggests that the FGF1 and IL-1␣ release pathways may be mechanistically linked [14]. Because amlexanox induces a Src-dependent and reversible disassembly of actin stress fibers [16], these data have suggested a role for the actin cytoskeleton in the regulation of FGF1 release [16]
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