FGF-1 known as acidic FGF (aFGF) is a 155 amino acid long non-glycosylated polypeptide. FGF-1 does not have a signal peptide and hence, their release is believed to be mediated by non-classical secretory pathways. Under normal physiological conditions, FGF-1 release has been barely detected. However, is found secreted in response to stress conditions such as heat shock, hypoxia [1, 2], serum starvation [3] and exposure to low-density lipoproteins [4]. Stress induces the release of the inactive disulfide bond-linked homodimeric form of FGF-1, which is dependent on p40-Syt1, S100A13 and Cu2+ ions [5-8]. FGF-1 is known to bind with different affinityto all the four members of the FGF receptors. The binding of FGF-1 to their cognate receptors in different cells induces the activation of diverse signaling pathways such as Ras/Raf/MAPK, PI3K/Akt, PLC, p38MAPK, and JNK pathways among others.

Binding of FGF-1 to the FGFRs in different cell types result in the formation of multiple complexes involving FRS2, GAB1, SOS1, PTPN11, SHC1 and GRB2 [9-14]. These complexes are critical to the subsequent activation of Ras GTPase [9, 12] which associates with Raf kinase [9] and further phosphorylation dependent activation of MAPK kinases 1/2 (MEK1/2) and subsequently MAPK1/3 (ERK2/1) [15, 16]. ERK pathway is involved in neurogenesis, adipocyte differentiation, cell proliferation, cholesterogenesis, and tumor invasion and metastasis induced by FGF-1 [16-20].

FRS2 complex through GAB1 initiates the activation of PI3K/AKT pathway to regulate processes including cell growth and survival, cell proliferation, and cell migration [21]. PI3K/Akt inhibitor-based assays have indicated the physiological role of this pathway in angiogenesis [22], lung development [23], maintenance of neuronal phenotype [24], neuroprotection [24] and ApoE-HDL secretion [25].

The c-jun N-terminal kinase (JNK) pathway is implicated in the regulation of cell cycle, cell survival and apoptosisinduced by FGF-1. p38MAPK signaling cascade, apart from being a stress response pathway, also plays a role in cell growth, differentiation, growth arrest and apoptosis. The JNK1/2 pathway was found to play a crucial role in neurogenesis and vascular remodeling [17, 26]. The specific functions of FGF-1 signaling mediated by p38 MAPK includes growth arrest, promotion of apoptosis in response to oxidative stress and formation of actin stress fibers in prostate cancer cells [27-29].

References

1. C. Mouta Carreira, M. Landriscina, S. Bellum. et al., "The comparative release of FGF1 by hypoxia and temperature stress," Growth Factors, vol. 18, no. 4, pp. 277-85, 2001.

2. A. Jackson, S. Friedman, X. Zhan. et al., "Heat shock induces the release of fibroblast growth factor 1 from NIH 3T3 cells," Proc Natl Acad Sci U S A, vol. 89, no. 22, pp. 10691-5, 1992.

3. J. T. Shin, S. R. Opalenik, J. N. Wehby. et al., "Serum-starvation induces the extracellular appearance of FGF-1," Biochim Biophys Acta, vol. 1312, no. 1, pp. 27-38, 1996.

4. N. M. Ananyeva, A. V. Tjurmin, J. A. Berliner. et al., "Oxidized LDL mediates the release of fibroblast growth factor-1," Arterioscler Thromb Vasc Biol, vol. 17, no. 3, pp. 445-53, 1997.

5. S. K. Mohan, S. G. Rani, S. M. Kumar. et al., "S100A13-C2A binary complex structure-a key component in the acidic fibroblast growth factor for the non-classical pathway," Biochem Biophys Res Commun, vol. 380, no. 3, pp. 514-9, 2009.

6. M. Landriscina, C. Bagala, A. Mandinova. et al., "Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress," J Biol Chem, vol. 276, no. 27, pp. 25549-57, 2001.

7. C. Mouta Carreira, T. M. LaVallee, F. Tarantini. et al., "S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro," J Biol Chem, vol. 273, no. 35, pp. 22224-31, 1998.

8. F. Tarantini, T. LaVallee, A. Jackson. et al., "The extravesicular domain of synaptotagmin-1 is released with the latent fibroblast growth factor-1 homodimer in response to heat shock," J Biol Chem, vol. 273, no. 35, pp. 22209-16, 1998.

9. M. Manuvakhova, J. V. Thottassery, S. Hays. et al., "Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells," Oncogene, vol. 25, no. 44, pp. 6003-14, 2006.

10. S. H. Ong, Y. R. Hadari, N. Gotoh. et al., "Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins," Proc Natl Acad Sci U S A, vol. 98, no. 11, pp. 6074-9, 2001.

11. Y. R. Hadari, H. Kouhara, I. Lax. et al., "Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation," Mol Cell Biol, vol. 18, no. 7, pp. 3966-73, 1998.

12. H. Kouhara, Y. R. Hadari, T. Spivak-Kroizman. et al., "A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway," Cell, vol. 89, no. 5, pp. 693-702, 1997.

13. M. Kanai, M. Goke, S. Tsunekawa. et al., "Signal transduction pathway of human fibroblast growth factor receptor 3. Identification of a novel 66-kDa phosphoprotein," J Biol Chem, vol. 272, no. 10, pp. 6621-8, 1997.

14. M. Mohammadi, I. Dikic, A. Sorokin. et al., "Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction," Mol Cell Biol, vol. 16, no. 3, pp. 977-89, 1996.

15. A. Willems-Widyastuti, B. M. Vanaudenaerde, R. Vos. et al., "Azithromycin Attenuates Fibroblast Growth Factors Induced Vascular Endothelial Growth Factor Via p38(MAPK) Signaling in Human Airway Smooth Muscle Cells," Cell Biochem Biophys, vol., no., 2011.

16. T. Nishida, J. Ito, Y. Nagayasu. et al., "FGF-1-induced reactions for biogenesis of apoE-HDL are mediated by src in rat astrocytes," J Biochem, vol. 146, no. 6, pp. 881-6, 2009.

17. C. W. Chen, C. S. Liu, I. M. Chiu. et al., "The signals of FGFs on the neurogenesis of embryonic stem cells," J Biomed Sci, vol. 17, no., pp. 33, 2010.

18. G. Lungu, L. Covaleda, O. Mendes. et al., "FGF-1-induced matrix metalloproteinase-9 expression in breast cancer cells is mediated by increased activities of NF-kappaB and activating protein-1," Mol Carcinog, vol. 47, no. 6, pp. 424-35, 2008.

19. F. S. Newell, H. Su, H. Tornqvist. et al., "Characterization of the transcriptional and functional effects of fibroblast growth factor-1 on human preadipocyte differentiation," FASEB J, vol. 20, no. 14, pp. 2615-7, 2006.

20. D. R. Newman, C. M. Li, R. Simmons. et al., "Heparin affects signaling pathways stimulated by fibroblast growth factor-1 and -2 in type II cells," Am J Physiol Lung Cell Mol Physiol, vol. 287, no. 1, pp. L191-200, 2004.

21. C. A. Castaneda, H. Cortes-Funes, H. L. Gomez. et al., "The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer," Cancer Metastasis Rev, vol. 29, no. 4, pp. 751-9, 2010.

22. R. Forough, B. Weylie, C. Patel. et al., "Role of AKT/PKB signaling in fibroblast growth factor-1 (FGF-1)-induced angiogenesis in the chicken chorioallantoic membrane (CAM)," J Cell Biochem, vol. 94, no. 1, pp. 109-16, 2005.

23. J. Wang, T. Ito, N. Udaka. et al., "PI3K-AKT pathway mediates growth and survival signals during development of fetal mouse lung," Tissue Cell, vol. 37, no. 1, pp. 25-35, 2005.

24. W. F. Lin, C. J. Chen, Y. J. Chang. et al., "SH2B1beta enhances fibroblast growth factor 1 (FGF1)-induced neurite outgrowth through MEK-ERK1/2-STAT3-Egr1 pathway," Cell Signal, vol. 21, no. 7, pp. 1060-72, 2009.

25. J. Ito, Y. Nagayasu, K. Okumura-Noji. et al., "Mechanism for FGF-1 to regulate biogenesis of apoE-HDL in astrocytes," J Lipid Res, vol. 48, no. 9, pp. 2020-7, 2007.

26. P. Li, S. Oparil, W. Feng. et al., "Hypoxia-responsive growth factors upregulate periostin and osteopontin expression via distinct signaling pathways in rat pulmonary arterial smooth muscle cells," J Appl Physiol, vol. 97, no. 4, pp. 1550-8; discussion 1549, 2004.

27. A. Raucci, E. Laplantine, A. Mansukhani. et al., "Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes," J Biol Chem, vol. 279, no. 3, pp. 1747-56, 2004.

28. J. Jiao, J. S. Greendorfer, P. Zhang. et al., "Alternatively spliced FGFR-1 isoform signaling differentially modulates endothelial cell responses to peroxynitrite," Arch Biochem Biophys, vol. 410, no. 2, pp. 187-200, 2003.

29. P. B. Mehta, C. N. Robson, D. E. Neal. et al., "Keratinocyte growth factor activates p38 MAPK to induce stress fibre formation in human prostate DU145 cells," Oncogene, vol. 20, no. 38, pp. 5359-65, 2001.