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phosphatases and kinase in cell signalling
1. Kinases and phosphatases work together to regulate cell signaling through phosphorylation and dephosphorylation of proteins. Kinases add phosphate groups while phosphatases remove them, allowing rapid and transient signaling responses. 2. There are three main classes of protein kinases - serine/threonine kinases, tyrosine kinases, and mixed kinases. Key kinase families discussed include PKA, PKC, calcium/calmodulin dependent kinases, receptor tyrosine kinases, and MAP kinases. 3. Phosphatases counteract kinase activity to terminate signaling responses in a timely manner. Important phosphatase families are PP1, PP2A, and calcineurin
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phosphatases and kinase in cell signalling
- 1. Kinases and Phosphatases incell signaling Giulio Taglialatela, Ph.D. John Sealy Professor and Vice Chair Dept. of Neurology Director, Mitchell Center for Neurodegenerative Diseases The University of Texas Medical Branch at Galveston
- 2. Signals are changesin homeostasis
- 3. To be recognizedas a signal, an event must be: 1. Sudden.
- 4. To be recognizedas a signal, an event must be: 1. Sudden. 2. Short-lived.
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- 7. The balanced activitybetween kinases and phosphatases provides sudden and (often) short lived modifications of proteins, resulting in effective signaling events
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- 11. Kinases share ahighly conserved catalytic core
- 12. Three classes ofprotein kinases 1. Serine/threonine kinases 2. Tyrosine kinases 3. Mixed kinases
- 13. Three classes ofprotein kinases 1. Serine/threonine kinases 2. Tyrosine kinases 3. Mixed kinases
- 14. Serine/threonine protein kinases 1.DAG/Ca2+ dependent (PKC) 2. cAMP-dependent (PKA) 3. Ca2+/Calmodulin-dependent (CaMKII)
- 15. 1. DAG/Ca2+ dependent(PKC) 2. cAMP-dependent (PKA) Serine/threonine protein kinases
- 16. G-PROTEIN-LINKED RECEPTORS Binding domain Dockingdomain CYTOSOL G-PROTEIN (inactive) α subunit β subunit γ subunit GDP
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- 34. G-PROTEIN-LINKED RECEPTORS CYTOSOL G-PROTEIN (active) Adenylatecyclase ATP cAMP
- 35. G-PROTEIN-LINKED RECEPTORS CYTOSOL G-PROTEIN (active) Adenylatecyclase ATP cAMP A-kinase
- 36. G-PROTEIN-LINKED RECEPTORS CYTOSOL G-PROTEIN (active) Adenylatecyclase ATP cAMP A-kinase Nucleus CREB
- 37. G-PROTEIN-LINKED RECEPTORS CYTOSOL G-PROTEIN (active) Adenylatecyclase ATP cAMP A-kinase Nucleus TranscriptionCREB CBP
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- 48. Serine/threonine protein kinases 3.Ca2+/Calmodulin-dependent (CaMKII)
- 49. Ca2+ -sensitive proteins: A storyof co-operation
- 50. Calmodulin A ubiquitous mediatorof Ca2+ signals Target protein
- 51. Calmodulin A ubiquitous mediatorof Ca2+ signals Target protein Increased affinity
- 52. Calmodulin A ubiquitous mediatorof Ca2+ signals Target protein
- 53. Calmodulin A ubiquitous mediatorof Ca2+ signals Target protein
- 54. Calmodulin A ubiquitous mediatorof Ca2+ signals Active target protein P
- 55. Calmodulin A ubiquitous mediatorof Ca2+ signals Active target protein P P Secondary cytosolic effects
- 56. Intracellular Ca2+ waves andoscillations
- 57. The ability ofintracellular Ca2+ stores to release Ca2+ is affected by the relative concentration of free cytosolic Ca2+ : It is increased by slightly elevated Ca2+ and decreased by very high Ca2+ concentrations. 0 2 4 6 8 10 12 Cytpsolic Ca2+ concentration ERCa2+release
- 84. Intracellular Ca2+ increases arecharacterized by: - frequency - amplitude (intensity) Consequently, cells have developed systems that will respond to either intensity or frequency (or both) of Ca2+ increases.
- 85. CaM Kinase II,a direct substrate for calmodulin, is a Ca2+ spike frequency detector In order for CaM Kinase to be fully active, each catalytic subunit must be autophosphorylated in a calmudulin-dependent fashion. Autophosphorylation of each subsequent subunit follows a co- operative kinetic.
- 86. CaM Kinase II,a direct substrate for calmodulin, is a Ca2+ spike frequency detector In order for CaM Kinase to be fully active, each catalytic subunit must be autophosphorylated in a calmudulin-dependent fashion. Autophosphorylation of each subsequent subunit follows a co- operative kinetic. calmudulin
- 87. CaM Kinase II,a direct substrate for calmodulin, is a Ca2+ spike frequency detector In order for CaM Kinase to be fully active, each catalytic subunit must be autophosphorylated in a calmudulin-dependent fashion. Autophosphorylation of each subsequent subunit follows a co- operative kinetic.
- 88. CaM Kinase II,a direct substrate for calmodulin, is a Ca2+ spike frequency detector In order for CaM Kinase to be fully active, each catalytic subunit must be autophosphorylated in a calmudulin-dependent fashion. Autophosphorylation of each subsequent subunit follows a co- operative kinetic.
- 89. CaM Kinase II,a direct substrate for calmodulin, is a Ca2+ spike frequency detector In order for CaM Kinase to be fully active, each catalytic subunit must be autophosphorylated in a calmudulin-dependent fashion. Autophosphorylation of each subsequent subunit follows a co- operative kinetic. Fully active CaM kinase
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- 99. time Fully active CaMKinase
- 101. CaM Kinase II,a direct substrate for calmodulin, is a Ca2+ spike frequency detector
- 102. Three classes ofprotein kinases 1. Serine/threonine kinases 2. Tyrosine kinases 3. Mixed kinases
- 103. The receptor tyrosinekinases
- 104. Binding domain tyrosine kinase domain Ligandsthat bind to specific RTK: FGF, NGF, IGF, BDNF, ……, XXXF
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- 106. P P P P PP P P Receptor autophosporylation
- 107. P The phophotyrosine domainacts as a docking site for proteins possessing a particular domain called SH2 SH2
- 108. P SH2 The SH2-containingprotein is then activated by either conformational change or by phosphorylation promoted by the receptor itself. P PLCγ PI3-K GAP (GEF) IRS
- 109. P SH2 P PLCγ −>PIP2/IP3/PKC PI3-K −> IP2/PIP3/PKB GAP (GEF) −> ras/MAPK IRS Multiple pathway activation
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- 112. Receptors associated withcytoplasmic tyrosine kinases JAK JAK cytosol nucleus Enzyme-linked receptors
- 113. Receptors associated withcytoplasmic tyrosine kinases JAK JAKP P P P STAT STAT P P cytosol nucleus SOCS Enzyme-linked receptors
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- 115. Receptor Serine/Threonine Kinases cytosol nucleus RII RI P PSMAD co-SMAD Enzyme-linked receptors
- 116. Three classes ofprotein kinases 1. Serine/threonine kinases 2. Tyrosine kinases 3. Mixed kinases
- 117. GTP MAP KINASE MAPK KINASE MAPKKKINASE P-SER P-SER P-SER P-THR P-THR P-TYR P-TYR Active Ras
- 119. GTP MAP KINASE MAPK KINASE MAPKKKINASE P-SER P-SER P-SER P-THR P-THR PKC P-TYR P-TYR Active Ras
- 120. MAP KINASE P-SER P-THR Direct: CREB.Indirect: JNK/c-jun DNA P-TYR
- 121. MAP KINASE P-SER P-THR Direct: CREB.Indirect: JNK/c-jun DNA RNA Pol II P-TYR
- 122. To be recognizedas a signal, an event must be: 1. Sudden. 2. Short-lived.
- 123. Who cleans upthe mess?
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- 125. Protein Phosphatases (PPT) Ser/ThrPPT Tyr PPT Mix PPT •MAPK PPT’s •CDC14’s •PTEN’s •CDC25’s •RTP’s •nonRTP’s •LMPT •Eya1-4 •PP1 •PP2A •PP2B (calcineurin) •PP2C
- 126. The phosphatase reactionis conserved among all phosphatases and does not require energy
- 127. Ser/Thr Protein Phosphatases Ca/CaM-indep. •PP2C•PP2B (calcineurin) •PP1 •PP2A Ca/CaM-dep.Mg/Mn-dep. Multimeric proteins formed by a catalytic subunit, a modulatory subunit and, in certain instances (PP2A), a scaffolding subunit
- 129. Both calcineurin andCaMKII are essential to modulate the function of the synapse in response to stimulatory Ca++ entry Both calcineurin and CaMKII are activated by binding to Ca++/calmodulin
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Editor's Notes
- #131 CaMKII is enriched at glutamatergic synapses and assemble into multimers Activated CaM binds to these units, allowing them to autophosphorylate at T286 A mutation is CaMKII that prevents autophosphorylation blocks LTP (Giese et al. 1998) Calcineurin is a phosphatase that comprises over 1% of total protein in the brain, and affects many neuronal functions. CaN has been demonstrated to regulate the activity of ion channels, neurotransmitter and hormone release, synaptic plasticity, and gene transcription (Yakel 1997). Studies where the gene is knocked out, knocked down, and overexpressed all result in impaired behavior in rodent models. This suggests that CaN is a critical protein, in moderation. If levels are too low or too high synaptic function can be compromised.