纖維母細胞生長因子是細胞有絲分裂、血管新生的重要因子。近年來發現它的分泌路徑並非藉由內質網/高基體系統的信號傳遞路徑，乃是透過適當機制直接由細胞內跑到細胞外。而這個機制必須先引導纖維母細胞生長因子透過細胞膜上的Tec kinase使自已被磷酸化後，再與磷脂醯肌醇 4,5 二磷酸在細胞膜上的特殊結合，之後引發一些下游功能反應，最後藉由細胞膜外的硫化肝素蛋白醣將之從細胞內吸引出去。而細胞膜上由膽固醇、神經鞘磷脂與磷脂醯肌醇 4,5 二磷酸形成一種特定的聚集區域，稱之為微區塊。本論文以表面電漿共振儀器，首先證明了纖維母細胞生長因子與磷脂醯肌醇 4,5 二磷酸的專一結合性，再進一步發現微區塊能有效地調控兩者的更強地專一結合。最後由螢光影像的實驗直接觀察為微區塊的情形，輔助性證明了前述論點。

1. Burgess, W.H. and T. Maciag, The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem, 1989. 58: p. 575-606.
2. Bikfalvi, A., et al., Biological roles of fibroblast growth factor-2. Endocrine Reviews, 1997. 18(1): p. 26-45.
3. Ago, H., et al., Crystal structure of basic fibroblast growth factor at 1.6 A resolution. J Biochem, 1991. 110(3): p. 360-3.
4. Simpson, R.J., et al., Primary structure of ovine pituitary basic fibroblast growth factor. FEBS Lett, 1987. 224(1): p. 128-32.
5. Lindner, M., et al., Probing the regulation of TASK potassium channels by PI(4,5)P2 with switchable phosphoinositide phosphatases. J Physiol, 2011. 589(Pt 13): p. 3149-3162.
6. Pochynyuk, O., et al., Molecular determinants of PI(4,5)P2 and PI(3,4,5)P3 regulation of the epithelial Na+ channel. J Gen Physiol, 2007. 130(4): p. 399-413.
7. Yu, Y.L., et al., EZH2 regulates neuronal differentiation of mesenchymal stem cells through PIP5K1C-dependent calcium signaling. J Biol Chem, 2011. 286(11): p. 9657-67.
8. Temmerman, K., et al., A direct role for phosphatidylinositol-4,5-bisphosphate in unconventional secretion of fibroblast growth factor 2. Traffic, 2008. 9(7): p. 1204-17.
9. Bastiaanse, E.M., K.M. Hold, and A. Van der Laarse, The effect of membrane cholesterol content on ion transport processes in plasma membranes. Cardiovasc Res, 1997. 33(2): p. 272-83.
10. Singer, S.J. and G.L. Nicolson, The fluid mosaic model of the structure of cell membranes. Science, 1972. 175(23): p. 720-31.
11. Harder, T., et al., Lipid domain structure of the plasma membrane revealed by patching of membrane components. J Cell Biol, 1998. 141(4): p. 929-42.
12. Brown, D.A. and E. London, Structure of detergent-resistant membrane domains: does phase separation occur in biological membranes? Biochem Biophys Res Commun, 1997. 240(1): p. 1-7.
13. Janes, P.W., S.C. Ley, and A.I. Magee, Aggregation of lipid rafts accompanies signaling via the T cell antigen receptor. J Cell Biol, 1999. 147(2): p. 447-61.
14. Nagafuku, M., et al., Reduction of glycosphingolipid levels in lipid rafts affects the expression state and function of glycosylphosphatidylinositol-anchored proteins but does not impair signal transduction via the T cell receptor. J Biol Chem, 2003. 278(51): p. 51920-7.
15. Cleves, A.E., et al., A new pathway for protein export in Saccharomyces cerevisiae. J Cell Biol, 1996. 133(5): p. 1017-26.
16. Cleves, A.E., Protein transports: the nonclassical ins and outs. Curr Biol, 1997. 7(5): p. R318-20.
17. Mignatti, P., T. Morimoto, and D.B. Rifkin, Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulum-Golgi complex. Journal of Cellular Physiology, 1992. 151(1): p. 81-93.
18. Yanagishita, M. and V.C. Hascall, Cell surface heparan sulfate proteoglycans. J Biol Chem, 1992. 267(14): p. 9451-4.
19. Ebert, A.D., et al., Tec-kinase-mediated phosphorylation of fibroblast growth factor 2 is essential for unconventional secretion. Traffic, 2010. 11(6): p. 813-26.
20. Engling, A., et al., Biosynthetic FGF-2 is targeted to non-lipid raft microdomains following translocation to the extracellular surface of CHO cells. Journal of Cell Science, 2002. 115(18): p. 3619-3631.
21. Nickel, W., S. Wegehingel, and C. Zehe, Rerouting of fibroblast growth factor 2 to the classical secretory pathway results in post-translational modifications that block binding to heparan sulfate proteoglycans. Febs Letters, 2008. 582(16): p. 2387-2392.
22. Zehe, C., et al., Cell-surface heparan sulfate proteoglycans are essential components of the unconventional export machinery of FGF-2. Proc Natl Acad Sci U S A, 2006. 103(42): p. 15479-84.
23. Nickel, W., Pathways of unconventional protein secretion. Curr Opin Biotechnol, 2010. 21(5): p. 621-6.
24. Gleizes, P.E., et al., Basic Fibroblast Growth-Factor (Fgf-2) Internalization through the Heparan-Sulfate Proteoglycans-Mediated Pathway - an Ultrastructural Approach. European Journal of Cell Biology, 1995. 66(1): p. 47-59.
25. Raman, R., et al., Structural specificity of heparin binding in the fibroblast growth factor family of proteins. Proc Natl Acad Sci U S A, 2003. 100(5): p. 2357-62.
26. Shing, Y., et al., Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science, 1984. 223(4642): p. 1296-9.
27. Davy, A., C. Feuerstein, and S.M. Robbins, Signaling within a caveolae-like membrane microdomain in human neuroblastoma cells in response to fibroblast growth factor. Journal of Neurochemistry, 2000. 74(2): p. 676-683.
28. Cheng, Z.J., et al., Membrane microdomains, caveolae, and caveolar endocytosis of sphingolipids. Mol Membr Biol, 2006. 23(1): p. 101-10.
29. Kurzchalia, T.V. and R.G. Parton, Membrane microdomains and caveolae. Curr Opin Cell Biol, 1999. 11(4): p. 424-31.
30. Golub, T. and P. Caroni, PI(4,5)P2-dependent microdomain assemblies capture microtubules to promote and control leading edge motility. J Cell Biol, 2005. 169(1): p. 151-65.
31. Green, R.J., et al., Surface plasmon resonance analysis of dynamic biological interactions with biomaterials. Biomaterials, 2000. 21(18): p. 1823-35.
32. Homola, J., Present and future of surface plasmon resonance biosensors. Anal Bioanal Chem, 2003. 377(3): p. 528-39.
33. Baird, G.S., D.A. Zacharias, and R.Y. Tsien, Biochemistry, mutagenesis, and oligomerization of DsRed, a red fluorescent protein from coral. Proc Natl Acad Sci U S A, 2000. 97(22): p. 11984-9.