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Regulation of cell function by FGFR3 receptor tyrosine kinase

Regulation of cell function by FGFR3 receptor tyrosine kinase. Pavel Krej ci Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA Institute of Experimental Biology, Masaryk University, Brno, Czech Republic. Fgfr3 +/-. Fgfr3 -/-. Fgfr3 +/-. Fgfr3 -/-. Tail.

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Regulation of cell function by FGFR3 receptor tyrosine kinase

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  1. Regulation of cell function by FGFR3 receptor tyrosine kinase Pavel Krejci Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA Institute of Experimental Biology, Masaryk University, Brno, Czech Republic

  2. Fgfr3+/- Fgfr3-/- Fgfr3+/- Fgfr3-/- Tail Cell 1996, 84(6):911-21.

  3. FGFR3-related skeletal dysplasias Thanatophoric Dysplasia Achondroplasia - short long bones - brachydactyly - macrocephaly - low nasal bridge - spinal stenosis - temporal lobe malformations Nat Genet 1995, 9:321-8..

  4. FGFR3-related skeletal dysplasia I AC II FGF binds here III TM TK STATURE Hypochondroplasia Achondroplasia SADDAN Thanatophoric Dysplasia

  5. Skeleton: hypochondroplasia, achondroplasia, thanatophoric dysplasia, SADDAN, Muenke syndrome Skin: epidermal nevi, seborrhaeic keratosis, acanthosis nigricans Cancer: multiple myeloma, bladder cancer, seminoma

  6. Exp Cell Res. 2004;297:152-64. J Cell Sci. 2005; 118: 5089-100. J Biol Chem. 2007 ;282:2929-36. Pediatr Res. 2007; 61(3):267-72. Invest New Drugs 2007; 25:391-95. PLoS One 2008; 3:e3961. J Cell Sci 2008; 121:272-81. Cell Signal 2009; 21:151-60. Hum Mol Genet. 2009; 18:227-40. J Biol Chem 2010; 285:20644-53. Bone 2010; 47:102-10. Leukemia 2011; 25:538-50. Human Mutation 2012; 33:29-41

  7. healthy TD resting proliferating hypertrophic bone

  8. FGFR3 inhibitschondrocyte proliferation by arresting their cell cycle in G1 phase 3H-thymidine (cpm x 103) % of cells FGF2 concentration (ng/ml) FGF2 (h) Exp Cell Res 2004, 297:152-64.

  9. FGFR3 alters the cartilage-like phenotype of chondrocytes control FGF2 FGF2 (h) control FGF2 M C 0.5 1 4 8 12 24 48 72 proMMP9 matureMMP9 aggrecan proMMP2 intermediate collagen II matureMMP2 collagen I pro MMP3/10 mature MMP3/10 GAPDH proMMP13 matureMMP13 J Cell Sci. 2005; 118: 5089-100.

  10. FGFR3 causes premature senescence in chondrocytes FGF2 control control FGF2 SA-b-gal Bone 2010; 47:102-10.

  11. FGFR3 arrests chondrocyte growth via RAS-ERK MAP kinase pathway FGF2 C1 C2 1’ 5’ 10’ 30’ 1h 2h 4h 8h P-Erk1/2 Erk1/2 P-p38 p38 P-PLCg1 PLCg1 Ras RasN17 cell colonies/100 cells (%) - F1 F10 F100 U0126 80 60 cells/wellx103 40 20 0 .001 .01 .1 1 10 100 Inhibitor concentration (mM) Exp Cell Res 2004, 297:152-64.

  12. SHP2 GRB2 SOS GRB2 SOS FGF2 FGFR3 GAB1 SHC FRS2 Ras Raf-1 MEK J Biol Chem 2007; 282:2929-36. Erk

  13. FGFR3 STAT1 CKI Growth arrest Skeletal dysplasia

  14. FGFR3 associates with STAT1 and acts as STAT1-kinase in chondrocytes FGFR3-K508M FGFR3-wt FGFR3-K650M GFP FGFR3 FGFR3 ? actin IP: STAT1 STAT1 FGFR3 WB ? STAT1 ? FGFR3-K650E FGFR3-wt CKI substrate: STAT1++ ++ ++ SU5402(mM)_ +_ _ +_ ATP++_++_ Growth arrest P-Y701-STAT1 Skeletal dysplasia STAT1 FGFR3

  15. J Cell Sci 2008;121:272-81.

  16. PLoS One 2008;3:e3961.

  17. Chronic FGF stimulus inhibits cytokine/STAT signaling in chondrocytes FGF2 IL6 STAT3-YFP DAPI merge DIC/merge IL11, LIF control FGFR3 IL6RA Shp2 Frs2 FGF2 2h gp130 Cish Socs1 Socs3 FGF2 48h STAT3 IL6 30m FGF2 48h nucleus STAT3 IL6 30m Cell Signal 2009;21:151-60.

  18. 20012012 FGFR3 IL6, LIF, IL11, IFNg FGFR3 CNP SOCS1/3 ? PKC NPR-B STAT1 Frs2, Gab1, SHC STAT1/3 STAT1 ? cGMP ? CKI ? Ras/Raf/MEK/Erk PKG proliferation growth arrest CKIMMP growth arrest matrix degradation

  19. FGF2: C1 15‘ 1h 3h 6h 12h 24h 48h 72h C2 C3 b-catenin actin Wnt

  20. submitted

  21. C-natriuretic peptide (CNP) wild-type wild-type Fgfr3Ach CNP Fgfr3Ach/CNP Kazuwa Nakao wild-type CNP

  22. 50 control 40 30 cells per well [x104] control 20 FGF2 10 FGF2 0 _ 0.1 0.2 0.5 1_ _ _ _CNP [mM] _ _ _ _ _ 10 100 200 500pCPT-cGMP [mM] control FGF2 control CNP

  23. FGF2 CNP FGFR3 NP-R FRS2 cGMP STOP Ras PKG Raf-1 Growth arrest MEK Erk Matrix degradation J Cell Sci. 2005; 118: 5089-100.

  24. Tocriscreen™ Mini Library A collection of 1120 biologically active compounds supplied as DMSO solutions.

  25. NF449 J Biol Chem 2010; 285:20644-53.

  26. Leukemia 2011. 25:538-50.

  27. Cedars-Sinai Medical Center Los Angeles, California Betty Mekikian Anie Aklian UCI, Irvine, California Leslie Thompson Tamara Kashiwada Lisa Salazar UCLA, Los Angeles, California Matthew Schibler Masaryk University, Brno, Czech Republic Jirina Prochazkova Vita Bryja Lukas Balek Tereza Spoustova Tereza Pospisilova INSERM U589, Toulouse, France Bernard Masri Vincent Fontaine

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