6j6y

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FGFR4 D2 - Fab complex

Structural highlights

6j6y is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.15Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FGFR4_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]

Publication Abstract from PubMed

The FGFR4/FGF19 signaling axis is over-activated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects. U3-1784 is a high affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo. The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.

Pre-clinical development of U3-1784, a novel FGFR4 antibody against cancer, and avoidance of its on-target toxicity.,Bartz R, Fukuchi K, Ohtsuka T, Lange T, Gruner K, Watanabe I, Hayashi S, Oda Y, Kawaida R, Komori H, Kashimoto Y, Wirtz P, Mayer JA, Redondo-Muller M, Saito S, Takahashi M, Hanzawa H, Imai E, Martinez A, Hanai M, Haussinger D, Chapman RW, Agatsuma T, Bange J, Abraham R Mol Cancer Ther. 2019 Jul 26. pii: 1535-7163.MCT-18-0048. doi:, 10.1158/1535-7163.MCT-18-0048. PMID:31350344[15]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Ron D, Reich R, Chedid M, Lengel C, Cohen OE, Chan AM, Neufeld G, Miki T, Tronick SR. Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. J Biol Chem. 1993 Mar 15;268(8):5388-94. PMID:7680645
  2. ↑ Vainikka S, Joukov V, Wennstrom S, Bergman M, Pelicci PG, Alitalo K. Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. J Biol Chem. 1994 Jul 15;269(28):18320-6. PMID:7518429
  3. ↑ Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996 Jun 21;271(25):15292-7. PMID:8663044
  4. ↑ Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol. 2001 Jul;3(7):650-7. PMID:11433297 doi:http://dx.doi.org/10.1038/35083041
  5. ↑ Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006 Jun 9;281(23):15694-700. Epub 2006 Apr 4. PMID:16597617 doi:10.1074/jbc.M601252200
  6. ↑ Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007 Sep 14;282(37):26687-95. Epub 2007 Jul 10. PMID:17623664 doi:10.1074/jbc.M704165200
  7. ↑ Citores L, Bai L, Sorensen V, Olsnes S. Fibroblast growth factor receptor-induced phosphorylation of STAT1 at the Golgi apparatus without translocation to the nucleus. J Cell Physiol. 2007 Jul;212(1):148-56. PMID:17311277 doi:10.1002/jcp.21014
  8. ↑ Haugsten EM, Malecki J, Bjorklund SM, Olsnes S, Wesche J. Ubiquitination of fibroblast growth factor receptor 1 is required for its intracellular sorting but not for its endocytosis. Mol Biol Cell. 2008 Aug;19(8):3390-403. doi: 10.1091/mbc.E07-12-1219. Epub 2008, May 14. PMID:18480409 doi:10.1091/mbc.E07-12-1219
  9. ↑ Wang J, Yu W, Cai Y, Ren C, Ittmann MM. Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia. 2008 Aug;10(8):847-56. PMID:18670643
  10. ↑ Triantis V, Saeland E, Bijl N, Oude-Elferink RP, Jansen PL. Glycosylation of fibroblast growth factor receptor 4 is a key regulator of fibroblast growth factor 19-mediated down-regulation of cytochrome P450 7A1. Hepatology. 2010 Aug;52(2):656-66. doi: 10.1002/hep.23708. PMID:20683963 doi:http://dx.doi.org/10.1002/hep.23708
  11. ↑ Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R, Gupte J, Hager T, Wang Z, Lindberg R, Li Y. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem. 2010 Feb 19;285(8):5165-70. doi: 10.1074/jbc.M109.068783. Epub 2009 , Dec 15. PMID:20018895 doi:http://dx.doi.org/10.1074/jbc.M109.068783
  12. ↑ Sugiyama N, Varjosalo M, Meller P, Lohi J, Chan KM, Zhou Z, Alitalo K, Taipale J, Keski-Oja J, Lehti K. FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15786-91. doi:, 10.1073/pnas.0914459107. Epub 2010 Aug 23. PMID:20798051 doi:http://dx.doi.org/10.1073/pnas.0914459107
  13. ↑ Nakamura M, Uehara Y, Asada M, Honda E, Nagai N, Kimata K, Suzuki M, Imamura T. Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho. J Biol Chem. 2011 Jul 29;286(30):26418-23. doi: 10.1074/jbc.M111.251140. Epub, 2011 Jun 8. PMID:21653700 doi:http://dx.doi.org/10.1074/jbc.M111.251140
  14. ↑ Sugiyama N, Varjosalo M, Meller P, Lohi J, Hyytiainen M, Kilpinen S, Kallioniemi O, Ingvarsen S, Engelholm LH, Taipale J, Alitalo K, Keski-Oja J, Lehti K. Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation. Cancer Res. 2010 Oct 15;70(20):7851-61. doi: 10.1158/0008-5472.CAN-10-1223. Epub , 2010 Sep 28. PMID:20876804 doi:http://dx.doi.org/10.1158/0008-5472.CAN-10-1223
  15. ↑ Bartz R, Fukuchi K, Ohtsuka T, Lange T, Gruner K, Watanabe I, Hayashi S, Oda Y, Kawaida R, Komori H, Kashimoto Y, Wirtz P, Mayer JA, Redondo-Muller M, Saito S, Takahashi M, Hanzawa H, Imai E, Martinez A, Hanai M, Haussinger D, Chapman RW, Agatsuma T, Bange J, Abraham R. Pre-clinical development of U3-1784, a novel FGFR4 antibody against cancer, and avoidance of its on-target toxicity. Mol Cancer Ther. 2019 Jul 26. pii: 1535-7163.MCT-18-0048. doi:, 10.1158/1535-7163.MCT-18-0048. PMID:31350344 doi:http://dx.doi.org/10.1158/1535-7163.MCT-18-0048

Contents


PDB ID 6j6y

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