Exploring mechanisms of FGF signalling through the lens of structural biology

Nature Reviews Molecular Cell Biology

Volumn 14, Issue 3, 2013, Pages 166-180

  Goetz, Regina ^a   Mohammadi, Moosa ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FIBROBLAST GROWTH FACTOR 1; FIBROBLAST GROWTH FACTOR 10; FIBROBLAST GROWTH FACTOR 19; FIBROBLAST GROWTH FACTOR 2; FIBROBLAST GROWTH FACTOR 23; FIBROBLAST GROWTH FACTOR 8; FIBROBLAST GROWTH FACTOR 9; FIBROBLAST GROWTH FACTOR RECEPTOR 1; FIBROBLAST GROWTH FACTOR RECEPTOR 2; FIBROBLAST GROWTH FACTOR RECEPTOR 3; FIBROBLAST GROWTH FACTOR RECEPTOR 4; HEPARAN SULFATE; KERATINOCYTE GROWTH FACTOR; KLOTHO PROTEIN; LIGAND;

ALTERNATIVE RNA SPLICING; BINDING AFFINITY; CARBOXY TERMINAL SEQUENCE; CELL LINEAGE; DIMERIZATION; EXTRACELLULAR MATRIX; HOMEOSTASIS; HUMAN; LIGAND BINDING; METABOLISM; MOLECULAR BIOLOGY; MORPHOGENESIS; MUTATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN MOTIF; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ANALYSIS; VITAMIN D METABOLISM;

ALTERNATIVE SPLICING; FIBROBLAST GROWTH FACTOR 8; FIBROBLAST GROWTH FACTOR 9; FIBROBLAST GROWTH FACTORS; GLUCURONIDASE; HEPARITIN SULFATE; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 1; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 2; RECEPTOR, FIBROBLAST GROWTH FACTOR, TYPE 3; RECEPTORS, FIBROBLAST GROWTH FACTOR; SIGNAL TRANSDUCTION;

EID: 84875421249     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3528     Document Type: Review

References (119)

1. Itoh, N. & Ornitz, D. M. Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J. Biochem. 149, 121-130 (2011).
2. Mohammadi, M., Olsen, S. K. & Ibrahimi, O. A. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev. 16, 107-137 (2005). (Pubitemid 40616111)
3. Itoh, N. & Ornitz, D. M. Evolution of the Fgf and Fgfr gene families. Trends Genet. 20, 563-569 (2004). (Pubitemid 39314564)
4. Schlessinger, J. et al. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol. Cell 6, 743-750 (2000).
5. Chen, H. et al. A crystallographic snapshot of tyrosine trans-phosphorylation in action. Proc. Natl Acad. Sci. USA 105, 19660-19665 (2008).
6. Furdui, C. M., Lew, E. D., Schlessinger, J. & Anderson, K. S. Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol. Cell 21, 711-717 (2006). (Pubitemid 43290737)
7. Gotoh, N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci. 99, 1319-1325 (2008). (Pubitemid 351761719)
8. Carpenter, G. & Ji, Q. Phospholipase C-γ as a signal-transducing element. Exp. Cell Res. 253, 15-24 (1999).
9. Bottcher, R. T. & Niehrs, C. Fibroblast growth factor signaling during early vertebrate development. Endocr. Rev. 26, 63-77 (2005). (Pubitemid 40209387)
10. Thisse, B. & Thisse, C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev. Biol. 287, 390-402 (2005). (Pubitemid 41636772)
11. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to cancer. Nature Rev. Cancer 10, 116-129 (2010).
12. Asada, M. et al. Glycosaminoglycan affinity of the complete fibroblast growth factor family. Biochim. Biophys. Acta 1790, 40-48 (2009).
13. Perrimon, N. & Bernfield, M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404, 725-728 (2000). (Pubitemid 30212391)
14. Goetz, R. et al. Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell. Biol. 27, 3417-3428 (2007). (Pubitemid 46685217)
15. Rapraeger, A. C., Krufka, A. & Olwin, B. B. Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science 252, 1705-1708 (1991). (Pubitemid 21917092)
16. Yayon, A., Klagsbrun, M., Esko, J. D., Leder, P. & Ornitz, D. M. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64, 841-848 (1991). (Pubitemid 121001170)
17. Ding, X. et al. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab. 16, 387-393 (2012).
18. Kurosu, H. et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282, 26687-26695 (2007). (Pubitemid 47501965)
19. Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by Klotho. J. Biol. Chem. 281, 6120-6123 (2006). (Pubitemid 43847540)
20. Nakatani, T., Ohnishi, M. & Razzaque, M. S. Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB J. 23, 3702-3711 (2009).
21. Ogawa, Y. et al. βKlotho is required for metabolic activity of fibroblast growth factor 21. Proc. Natl Acad. Sci. USA 104, 7432-7437 (2007). (Pubitemid 47185923)
22. Tomiyama, K. et al. Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proc. Natl Acad. Sci. USA 107, 1666-1671 (2010).
23. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770-774 (2006). (Pubitemid 44949607)
24. Dorey, K. & Amaya, E. FGF signalling: diverse roles during early vertebrate embryogenesis. Development 137, 3731-3742 (2010).
25. Hart, A. W., Baeza, N., Apelqvist, A. & Edlund, H. Attenuation of FGF signalling in mouse β-cells leads to diabetes. Nature 408, 864-868 (2000). (Pubitemid 32016097)
26. Jonker, J. W. et al. A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 485, 391-394 (2012).
27. Zhou, M. et al. Fibroblast growth factor 2 control of vascular tone. Nature Med. 4, 201-207 (1998). (Pubitemid 28137375)
28. Sakaue, H. et al. Requirement of fibroblast growth factor 10 in development of white adipose tissue. Genes Dev. 16, 908-912 (2002). (Pubitemid 34408540)
29. Potthoff, M. J., Kliewer, S. A. & Mangelsdorf, D. J. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 26, 312-324 (2012).
30. Quarles, L. D. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nature Rev. Endocrinol. 8, 276-286 (2012).
31. Razzaque, M. S. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nature Rev. Endocrinol. 5, 611-619 (2009).
32. Long, Y. C. & Kharitonenkov, A. Hormone-like fibroblast growth factors and metabolic regulation. Biochim. Biophys. Acta 1812, 791-795 (2011).
33. Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nature Rev. Drug Discov. 8, 235-253 (2009).
34. Wilkie, A. O. Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev. 16, 187-203 (2005). (Pubitemid 40616116)
35. Goetz, R. et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc. Natl Acad. Sci. USA 107, 407-412 (2010).
36. Kalinina, J. et al. Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix. Mol. Cell. Biol. 29, 4663-4678 (2009).
37. Olsen, S. K. et al. Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain. Genes Dev. 20, 185-198 (2006). (Pubitemid 43112937)
38. Plotnikov, A. N. et al. Crystal structure of fibroblast growth factor 9 reveals regions implicated in dimerization and autoinhibition. J. Biol. Chem. 276, 4322-4329 (2001).
39. Yeh, B. K. et al. Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors. Proc. Natl Acad. Sci. USA 100, 2266-2271 (2003). (Pubitemid 36297488)
40. Gallagher, J. T. Heparan sulfate: growth control with a restricted sequence menu. J. Clin. Invest. 108, 357-361 (2001). (Pubitemid 32730779)
41. Chen, Y., Mohammadi, M. & Flanagan, J. G. Graded levels of FGF protein span the midbrain and can instruct graded induction and repression of neural mapping labels. Neuron 62, 773-780 (2009).
42. Harada, M. et al. FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nature Genet. 41, 289-298 (2009).
43. Makarenkova, H. P. et al. Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis. Sci. Signal. 2, ra55 (2009).
44. Qu, X. et al. Lacrimal gland development and Fgf10-Fgfr2b signaling are controlled by 2-O-and 6-O-sulfated heparan sulfate. J. Biol. Chem. 286, 14435-14444 (2011).
45. Qu, X. et al. Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development. Development 139, 2730-2739 (2012).
46. Murakami, H. et al. Elbow knee synostosis (Eks): a new mutation on mouse chromosome 14. Mamm. Genome 13, 341-344 (2002). (Pubitemid 34686756)
47. Crossley, P. H. & Martin, G. R. The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development 121, 439-451 (1995).
48. Gemel, J., Gorry, M., Ehrlich, G. D. & MacArthur, C. A. Structure and sequence of human FGF8. Genomics 35, 253-257 (1996). (Pubitemid 26236178)
49. MacArthur, C. A. et al. FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development. Development 121, 3603-3613 (1995).
50. Xu, J., Lawshe, A., MacArthur, C. A. & Ornitz, D. M. Genomic structure, mapping, activity and expression of fibroblast growth factor 17. Mech. Dev. 83, 165-178 (1999). (Pubitemid 29302091)
51. Sato, T., Araki, I. & Nakamura, H. Inductive signal and tissue responsiveness defining the tectum and the cerebellum. Development 128, 2461-2469 (2001). (Pubitemid 32685088)
52. Lee, S. M., Danielian, P. S., Fritzsch, B. & McMahon, A. P. Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. Development 124, 959-969 (1997). (Pubitemid 27139916)
53. Liu, A., Losos, K. & Joyner, A. L. FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Development 126, 4827-4838 (1999).
54. Christen, B. & Slack, J. M. FGF-8 is associated with anteroposterior patterning and limb regeneration in Xenopus. Dev. Biol. 192, 455-466 (1997). (Pubitemid 28066947)
55. Fletcher, R. B., Baker, J. C. & Harland, R. M. FGF8 spliceforms mediate early mesoderm and posterior neural tissue formation in Xenopus. Development 133, 1703-1714 (2006). (Pubitemid 43810977)
56. Falardeau, J. et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J. Clin. Invest. 118, 2822-2831 (2008).
57. Shimada, T. et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143, 3179-3182 (2002). (Pubitemid 34809892)
58. White, K. E. et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 60, 2079-2086 (2001). (Pubitemid 33070451)
59. Seidah, N. G. & Prat, A. The biology and therapeutic targeting of the proprotein convertases. Nature Rev. Drug Discov. 11, 367-383 (2012).
60. Gram Schjoldager, K. T. et al. A systematic study of site-specific GalNAc-type O-glycosylation modulating proprotein convertase processing. J. Biol. Chem. 286, 40122-40132 (2011).
61. White, K. E. et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nature Genet. 26, 345-348 (2000).
62. Frishberg, Y. et al. Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J. Bone Miner. Res. 22, 235-242 (2007). (Pubitemid 46167794)
63. Kato, K. et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J. Biol. Chem. 281, 18370-18377 (2006). (Pubitemid 44035494)
64. Hsu, Y. R. et al. Human keratinocyte growth factor recombinantly expressed in Chinese hamster ovary cells: isolation of isoforms and characterization of post-translational modifications. Protein Expr. Purif. 12, 189-200 (1998).
65. Kim, G. Y. et al. HtrA1 is a novel antagonist controlling FGF signaling via cleavage of FGF8. Mol. Cell. Biol. 4 Sept 2012 (doi:10.1128/MCB.00872-12).
66. Avivi, A., Yayon, A. & Givol, D. A novel form of FGF receptor-3 using an alternative exon in the immunoglobulin domain III. FEBS Lett. 330, 249-252 (1993). (Pubitemid 23276333)
67. Chellaiah, A. T., McEwen, D. G., Werner, S., Xu, J. & Ornitz, D. M. Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1. J. Biol. Chem. 269, 11620-11627 (1994). (Pubitemid 24200387)
68. Johnson, D. E., Lu, J., Chen, H., Werner, S. & Williams, L. T. The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol. Cell. Biol. 11, 4627-4634 (1991). (Pubitemid 21895859)
69. Miki, T. et al. Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc. Natl Acad. Sci. USA 89, 246-250 (1992).
70. Orr-Urtreger, A. et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev. Biol. 158, 475-486 (1993). (Pubitemid 23243904)
71. Yan, G., Fukabori, Y., McBride, G., Nikolaropolous, S. & McKeehan, W. L. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol. Cell. Biol. 13, 4513-4522 (1993). (Pubitemid 23220358)
72. Yayon, A. et al. A confined variable region confers ligand specificity on fibroblast growth factor receptors: implications for the origin of the immunoglobulin fold. EMBO J. 11, 1885-1890 (1992).
73. Wuechner, C., Nordqvist, A. C., Winterpacht, A., Zabel, B. & Schalling, M. Developmental expression of splicing variants of fibroblast growth factor receptor 3 (FGFR3) in mouse. Int. J. Dev. Biol. 40, 1185-1188 (1996). (Pubitemid 27072812)
74. Zhang, X. et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J. Biol. Chem. 281, 15694-15700 (2006).
75. Alarid, E. T. et al. Keratinocyte growth factor functions in epithelial induction during seminal vesicle development. Proc. Natl Acad. Sci. USA 91, 1074-1078 (1994). (Pubitemid 24048511)
76. Colvin, J. S., White, A. C., Pratt, S. J. & Ornitz, D. M. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development 128, 2095-2106 (2001). (Pubitemid 32600470)
77. De Moerlooze, L. et al. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis. Development 127, 483-492 (2000). (Pubitemid 30093396)
78. Min, H. et al. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev. 12, 3156-3161 (1998). (Pubitemid 28496260)
79. Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nature Genet. 21, 138-141 (1999). (Pubitemid 29036301)
80. Xu, X. et al. Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125, 753-765 (1998). (Pubitemid 28108099)
81. Zhang, X. et al. Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development. Development 133, 173-180 (2006). (Pubitemid 43169331)
82. Plotnikov, A. N., Hubbard, S. R., Schlessinger, J. & Mohammadi, M. Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Cell 101, 413-424 (2000).
83. Wang, F., Kan, M., Xu, J., Yan, G. & McKeehan, W. L. Ligand-specific structural domains in the fibroblast growth factor receptor. J. Biol. Chem. 270, 10222-10230 (1995).
84. Lajeunie, E. et al. FGFR2 mutations in Pfeiffer syndrome. Nature Genet. 9, 108 (1995).
85. Nagase, T., Nagase, M., Hirose, S. & Ohmori, K. Mutations in fibroblast growth factor receptor 2 gene and craniosynostotic syndromes in Japanese children. J. Craniofac. Surg. 9, 162-170 (1998). (Pubitemid 28152200)
86. Ibrahimi, O. A. et al. Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities. Hum. Mol. Genet. 13, 2313-2324 (2004). (Pubitemid 39359928)
87. Olsen, S. K. et al. Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity. Proc. Natl Acad. Sci. USA 101, 935-940 (2004). (Pubitemid 38160562)
88. Plotnikov, A. N., Schlessinger, J., Hubbard, S. R. & Mohammadi, M. Structural basis for FGF receptor dimerization and activation. Cell 98, 641-650 (1999). (Pubitemid 29418955)
89. Stauber, D. J., DiGabriele, A. D. & Hendrickson, W. A. Structural interactions of fibroblast growth factor receptor with its ligands. Proc. Natl Acad. Sci. USA 97, 49-54 (2000). (Pubitemid 30055782)
90. Goetz, R. et al. Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. J. Biol. Chem. 287, 29134-29146 (2012).
91. Ito, S., Fujimori, T., Hayashizaki, Y. & Nabeshima, Y. Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure. Biochim. Biophys. Acta 1576, 341-345 (2002). (Pubitemid 34655778)
92. Ito, S. et al. Molecular cloning and expression analyses of mouse βKlotho, which encodes a novel Klotho family protein. Mech. Dev. 98, 115-119 (2000).
93. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45-51 (1997).
94. Yahata, K. et al. Molecular cloning and expression of a novel Klotho-related protein. J. Mol. Med. (Berl.) 78, 389-394 (2000).
95. Henrissat, B. A classification of glycosyl hydrolases based on amino acid sequence similarities. Biochem. J. 280, 309-316 (1991).
96. Henrissat, B. & Bairoch, A. New families in the classification of glycosyl hydrolases based on amino acid sequence similarities. Biochem. J. 293, 781-788 (1993). (Pubitemid 23244564)
97. Henrissat, B. & Bairoch, A. Updating the sequence-based classification of glycosyl hydrolases. Biochem. J. 316, 695-696 (1996). (Pubitemid 26182174)
98. Fon Tacer, K. et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol. 24, 2050-2064 (2010).
99. Goetz, R. et al. Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Mol. Cell. Biol. 32, 1944-1954 (2012).
100. Kharitonenkov, A. et al. FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J. Cell. Physiol. 215, 1-7 (2008). (Pubitemid 351363185)
101. Li, S. A. et al. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct. Funct. 29, 91-99 (2004). (Pubitemid 40260033)
102. Machado, M. F. et al. Regulation and action of fibroblast growth factor 17 in bovine follicles. J. Endocrinol. 202, 347-353 (2009).
103. Portela, V. M. et al. Expression and function of fibroblast growth factor 18 in the ovarian follicle in cattle. Biol. Reprod. 83, 339-346 (2010).
104. Gabrielsson, B. G. et al. Depot-specific expression of fibroblast growth factors in human adipose tissue. Obes. Res. 10, 608-616 (2002). (Pubitemid 135688259)
105. Jaskoll, T. et al. FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis. BMC Dev. Biol. 5, 11 (2005).
106. Mailleux, A. A. et al. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 129, 53-60 (2002). (Pubitemid 34863775)
107. Qiao, J. et al. FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development 126, 547-554 (1999). (Pubitemid 29082041)
108. Terauchi, A. et al. Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature 465, 783-787 (2010).
109. Dutchak, P. A. et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148, 556-567 (2012).
110. Tontonoz, P. & Spiegelman, B. M. Fat and beyond: the diverse biology of PPARγ. Annu. Rev. Biochem. 77, 289-312 (2008).
111. Hotta, Y. et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology 150, 4625-4633 (2009).
112. Ming, A. Y. et al. Dynamics and distribution of Klothoβ (KLB) and fibroblast growth factor receptor-1 (FGFR1) in living cells reveal the fibroblast growth factor-21 (FGF21)-induced receptor complex. J. Biol. Chem. 287, 19997-20006 (2012).
113. Kouhara, H. et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89, 693-702 (1997). (Pubitemid 27516172)
114. Lamothe, B. et al. The docking protein Gab1 is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway. Mol. Cell. Biol. 24, 5657-5666 (2004). (Pubitemid 38787952)
115. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96, 857-868 (1999). (Pubitemid 29165088)
116. Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231-241 (1997). (Pubitemid 27456390)
117. Hartwig, J. H. et al. MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium-calmodulin. Nature 356, 618-622 (1992).
118. Li, H., Rao, A. & Hogan, P. G. Interaction of calcineurin with substrates and targeting proteins. Trends Cell Biol. 21, 91-103 (2011).
119. Ye, S. et al. Structural basis for interaction of FGF-1, FGF-2, and FGF-7 with different heparan sulfate motifs. Biochemistry 40, 14429-14439 (2001). (Pubitemid 33111725)