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Two receptor classes Receptor tyrosine kinases (RTKs)

Published byClarence Harper Modified over 9 years ago

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Presentation on theme: "Two receptor classes Receptor tyrosine kinases (RTKs)"— Presentation transcript:

1 Two receptor classes Receptor tyrosine kinases (RTKs)
Ligand induced dimerization Autophosphorylation Substrate phosphorylation Adapter proteins G-Protein coupled receptors (GPCRs) Ligand induced activation Guanine exchange factor (GEF) Second messenger cascade

2 Hierarchical overview
Signaling molecule G-Protein coupled receptor Receptor tyrosine kinase Nucleotide cyclases Phospholipases Kinases Second messengers Effector kinase cascades Gene expression Protein activity Phenotypic behavior

3 eg: Insulin Generated by pancreas Acts on muscle & other tissues
Multiple mechanisms Multiplicative mechanisms IR IRS-1 Shc Glut4 translocation Rab 8/14 AS160 PI3-K GRB2 Protein synthesis mTOR Akt Raf MEK Gene transcription Elk-1 MAPK

4 eg: Prostaglandin E2 Locally generated Inflammatory mediator Labor EPR
Gq Gi L-type Ca2+ Potentiation PKC PLC AC In/Decreased Contractility CaM Ca2+ Raf MEK Gene transcription Elk-1 MAPK

5 Receptor tyrosine kinases
Single pass transmembrane protein Ligand induces dimerization Kinase activity Autophosphorylation Complex formation FGF receptor binding FGF FGF Cytoplasmic

6 Phosphotyrosine binding
Phospho-Tyrosine Binding (PTB) Src homology (SH2, SH3) domain Common amino acid motif Phosphotyrosine binding pocket Phosphorylation dependent association Interaction with both pY and nearby residues Sh2 domain from Itk PDB:2etz xnnletyewy nksisrdkae kllldtgkeg afmvrdsrtp gtytvsvftk aiisenpcik hyhiketnds pkryyvaeky vfdsiplliq yhqynggglv trlrypvcg

7 Phosphotyrosine binding
Recruit biologically active molecules Phospholipases, PI3-K GTPase modulators (Sos, DOCK180) Adapter proteins (Grb-2, Shc, Nck, Crk) Increase effective availability of substrate Membrane phospholipids Other pY-bound proteins Increase biological activity Phosphorylation dependent activation pY-binding dependent activation

8 eg: FGFR phosphorylation
DNA Synthesis cdc related kinase Crk Y463 Y583 Shc Y653 PLC Y730 GRB2 Y766 IP3+DAG Ca2+, motility Sos MAPK growth

9 Modulation & Termination
Receptor antagonists Combinatorial control Termination Protein Tyrosine Phosphatases (PTPs) Internalization Ubiquitinylation

10 EGFR signaling network
Lemmon & Schlessinger 2010

11 G-Protein Coupled Receptor
GPCR are 7 pass transmembrane proteins Rhodopsin/b-adrenergic Secretin/vasointestinal peptide Metabotropic glutamate Ga Guanine exchange factor (GEF) Heterotrimeric G-Protein Ga - Gbg binding Can function monomeric Also dimerize

12 GPCR Receptor ligation catalyzes GDP-GTP exchange on Ga
GTP bound Ga dissociates from Gbg Ga modulates secondary signaling Gbg may also modulate secondary signaling Unligated Receptor Bound Receptor Ga-GDP Ga-GTP Gbg Gbg

13 G-a mediated signaling
Acylated, membrane bound Ga and target Ga allosterically regulated by GTP Target allosterically regulated by Ga Membrane association decreases diffusion distance Gas Adenylate cyclase GTP Substrate ATP

14 G Protein Classes G Protein Agonist Effector Gs Ubiquitous
Adenylyl cyclase (AC) Gt Photons cGMP phosphodiesterase Gq ACh, epinepherine PLC Gi Ca2+ channels, AC (-) Gz Dopamine, adenosine AC(-), K+ channel (-) Gb K+ Channel, PLA2, AC, PLC Metabotropic neurotransmitter receptors are all GPCRs

15 General Scheme Agonist binding triggers nucleotide exchange
G subunits dissociate Ga binds effectors GTP hydrolysis restores inactive state Effector may be a GAP

16 Receptor regulation, negative feedback
Activity depends on association of intracellular loops Rapid desensitization G-protein coupled Receptor Kinases (GRK) PKA, PKC Internalization Arrestin Clathrin/caveolae Long-term desensitization Downregulation G-Protein deactivation

17 Clathrin-mediated internalization
GPCR Kinase (GRK) Receptor inactivation Gbg-binding Distributed signaling Ga Ligand Receptor GRK B-arrestin Clathrin-mediated internalization Penela & al 2007

18 G-Protein regulation In vivo signaling much faster than reconstituted systems Regulator of G-protein Signaling (RGS) Ga GAP Esp Gi, Gq PLCb, RhoGEF are RGS Kinetics Ga: minutes Ga-RGS: tenths of second

19 eg: Synaptic remodeling
Rearrangement of neural networks Synaptic reinforcement Long term potentiation Remodeling of dendritic spines Calcium dependent cell motility Stimulation of cultured neuron with NMDA results in rapid development of a new dendritic spine Goldin, et al., 2001

20 Glutamate - Ga12/13 Metabotropic glutamate receptor 1 is Ga12 coupled GPCR Ga12 is a Rho-GEF RhoA small GTPases RhoA, Rac1 and Cdc42 Subcellular transport Cytoskeletal remodeling Actin filament growth(mDia) Stress fiber anchorage (ROCK) Kinectin ROCK mDia

21 eg: Competitive control of AC (heart)
Sympathetic NS (fight or flight) Parasympathetic NS (rest or relax) Increased depolarization cAMP increases Ca2+ influx Increased force Reduced Ca2+ efflux Increased Ca2+ influx Isoproterenol-induced contractile desensitization ~20 min Wettschureck & Offermanns, 2005 Huang & al., 2011

22 b-adrenergic heart failure
Persistent b-stimulation induces heart failure Reduced b1 receptor Exaggerated BARK/GRK2 GRK2 knockout reduces mortality Cardiac, inducible GRK2 ko before or after MI improves long-term survival Raake & al 2008

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