Signaling pathways Katka Hemalov´a sybilasystemsbiologylaboratory March 20, 2014 1 Signaling pathways 2 FGFR pathway 3 Yamada et al. model Signals Cooper et al., The Cell: A Molecular Approach, 4th edition, 2006 Cell signaling Alberts et al., Molecular biology of the Cell, 5th edition, 2007 Response time Alberts et al., Molecular biology of the Cell, 5th edition, 2007 Receptors Alberts et al., Molecular biology of the Cell, 5th edition, 2007 Signal transduction through molecular switches Other ways to switch a protein on/off: binding of another signaling protein, cAMP, Ca2+ or by another modification (e.g. ubiquitylation) Alberts et al., Molecular biology of the Cell, 5th edition, 2007 Scaffold proteins Signaling proteins in close proximity Fast, efficient, selective response to an extracellular signal Avoiding unwanted cross-talk Alberts et al., Molecular biology of the Cell, 5th edition, 2007 The three largest classes of cell-surface receptor Ion-channel-coupled receptors G-protein-coupled receptors Enzyme-coupled receptors Ion-channel-coupled receptors Alberts et al., Molecular biology of the Cell, 5th edition, 2007 G-protein coupled receptors http://www.rcsb.org/pdb/101/motm.do?momID=58 cAMP activates Protein kinase A Cooper et al., The Cell: A Molecular Approach, 4th edition, 2006 Enzyme-coupled recepetors Campbell N., Biology, 5th edition, 2000 Enzyme-coupled recepetors Alberts et al., Molecular biology of the Cell, 5th edition, 2007 SH2 domain (”SRC-Homology 2 domain”) crucial part of adaptors (Grb2, Shc, Crk, ...) Cooper et al., The Cell: A Molecular Approach, 4th edition, 2006 Grb2 and Ras pathway Grb2-SOS complex preexist in cytoplasm Weinberg, R., The Biology of Cancer, Garland Science, 2007 Ras pathway (MAPK pathway) http://oregonstate.edu/instruct/bb492/fignames/ras3.html Fibroblast growth factor receptor 3 (FGFR3) Enzyme-coupled receptor Growth and proliferation inhibition Mutation that cause achondroplasia act by exaggerating the negative regulatory functions of FGFR3 Deng et al.,Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth, Cell, 1996 FGFR3-related skeletal dysplasia FGFRs employ several signaling pathways, MAPK pathway is one of them Leaderich M. B., Horton W. A., Achondroplasia: pathogenesis and implications for future treatment, Curr Opin Pediatr, 2010 Constitutive activation of ERK Mutated FGFR3 induces constitutive activation of the MAPK pathway in chondrocytes Disease results from increased signal from the mutant receptor FGFRs recruit their downstream adaptors (GAB1, SHC, FRS2, etc.) EGF vs. FGF pathway model schema (Yamada et al., 2004) Grb2-SOS binds EGFR directly or through Shc Grb2-SOS binds FGFR through FRS2 Yamada S., Taketomi T., Yoshimura A., Model analysis of difference between EGF pathway and FGF pathway, BBRC, 2004 EGF vs. FGF pathway (Yamada et al., 2004) Duration of ERK activation determines the cell response EGF induces transient ERK activation FGF induces transient and sustained ERK activation What is the reason for difference in time course? Dependency on Shc and FRS2 initial concentration Grb2-SOS binds EGFR directly or through Shc → ERK activation is limited by concentration of receptor [EGFR2P] + [Grb2-SOS] ↔ [EGFR2P-Grb2-SOS] [EGFR2P-ShcP] + [Grb2-SOS] ↔ [EGFR2P-ShcP-Grb2-SOS] Grb2-SOS binds FGFR through FRS2 → signal amplification [FGFR2P] + [FRS] ↔ [FGFR2P-FRS] [FGFR2P-FRS] → [FGFR2P] + [FRSP] [FRSP] + [Grb2-SOS] ↔ [FRSP-Grb2-SOS] EGF vs. FGF pathway summary Differences in mechanism of interaction between receptors and first adapters FRS2 and sustained ERK activation (more Grb2-SOS complexes are recruited)