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The MAPK pathway is a signal transduction pathway that responds to extracellular stimuli and regulates various cellular processes. It involves a phosphorylation cascade from MAPKKK to MAPKK to MAPK that ultimately regulates transcription factors and gene expression. Second messengers like cAMP, IP3, and calcium amplify extracellular signals and allow cross-talk between different pathways. The MAPK pathway controls processes like cell growth, division, survival, and metabolism.
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- 1. Mitogen-activated (stimulates mitosis) ProteinKinase (MAPK) Pathway Mohammed Kaleem Khan (Ph.D. Candidate) ID:1802147 Department of Biochemistry Faculty of Life Science King Abdulaziz University, KSA
- 2. Second messengers •cAMP secondmessenger • Phosphatidylinositol cycle •Sphingolipid •Eicosanoids •Calcium as a second messenger •Others MAP kinase pathway Activity of MAP kinase Role in signaling Cross functions
- 3. MAPKs Group of proteinSerine/threonine Kinases Activated in response to a variation of extracellular stimuli Mediate signal transduction from the cell surface to the nucleus Found inside many cellular compartments Provide a physical link in the signal transduction pathway from the cytoplasm to the nucleus Regulate various transcriptional actions in Eukaryotic organism. Controls cell growth, to cell division (mating in haploid yeast).
- 4. Basic MAPK Pathwayhas the following Mitogen Receptor MAPKKK MAPKK/MEK MAPK/ERK Transcription factor DNA sequence Cell Membrane G-protein (GTPase) Nucleus
- 6. Ras Activation ofMAP Kinase Ras activates MAP kinase via a phosphorylation cascade that proceeds from Ras to Raf kinase, to MEK kinase, and finally to MAP kinase. MAP kinase then dimerizes and enters the nucleus.
- 7. Regulation of geneexpression through MAPK signaling pathways Phosphorylation of transcription factors, thereby enhancing their activity: Gene Expression Metabolism Cell Division Cell Morphology Cell Survival Regulate Cancer, Inflammation and Cardiovascular disease. Negatively regulated transcription factors by promoting their retention in the cytoplasm upon phosphorylation active dephosphorylation of these factors is needed for their migration to the nucleus Translational regulation Regulation of protein degradation phosphorylation of transcription factors impedes their ubiquitination and thus their degradation by the Proteasome
- 8. Recognition of areaction partner by a kinase or phosphatase
- 9. Signal Transduction and KinasePathways Nucleus MAP kinase, • Transcription factors – Bind consensus sequence on promoter – May form complexes – May itself be transcribed following cellular activation Adaptor proteins Effector enzymes
- 10. Second Messenger An extracellularsignaling molecule is termed “first messenger” First messenger → production of small and transient signaling molecule on inside of the cell → referred to as second messenger → intracellular response The second messenger is used to define “signalling molecules which are found to be produced by cells in response to the perception of the first message” (extracellular ligand).
- 11. Feature of IntracellularMessenger need amplification For example, one molecule bind to the exterior surface of the cells →activation of hundreds or thousands of enzyme molecules inside the cell→ catalyze many rounds of reaction → produced amplification of signal
- 12. Mechanism of Actionof Hydrophilic Messengers Hydrophilic messengers cannot cross the cell membrane. This restriction forces them into a 'classical' method of messenger action, namely the production of intracellular second messengers which are responsible for the effects of the various messengers. serve to amplify a signal Molecules whose presence is a signal Synthesized or released from storage Act as intracellular ligands
- 14. This second messengerthen is responsible for the displays of all of the effects of the primary messenger inside the cell. Cascades have certain advantages to include signal divergence, convergence and amplification. The resultant ligand receptor complex is coupled to an enzyme found on the internal surface of the cell membrane and stimulates the conversion of some metabolite into a second messenger. Mostly, the second messenger acts by stimulating or inhibiting protein phosphorylation/dephosphorylation cascades. Ligand binds to receptors located on the external surface of the plasma membrane.
- 15. Primary amplifier enzymes: adenylylcyclase → cyclic AMP from ATP guanylyl cyclase → cyclic GMP from GTP phospholipase C (PLC) cleaves phosphatidylinositol bisphosphate (PIP2) → diacylglycerol (DAG) — diffuses in membrane inositol trisphosphate (IP3) — released into cytosol Secondary amplifier enzymes: protein kinase A (PKA) protein kinase G (PKG) protein kinase C (PKC) calcium-calmodulin kinase (Ca-CM-K)
- 23. Phosphatidylinositol Cycle The PI-cycleis a series of enzyme-catalyzed biochemical reactions that form a cyclical process, which the intermediates pathway of second messenger. Found in the plasma membrane. It is an vital constituent of a signalling pathway in the cell nucleus Produces inositol triphosphate that is a vital ligand in opening calcium channels Functions Growth, cell survival, proliferation, cytoskeletal rearrangement, intracellular vesicle trafficking, and cell metabolism Regulates intracellular calcium levels
- 27.
- 28. Anti inflammatory Drugsinhibit Eicosanoid SynthesisAnti inflammatory Drugs inhibit Eicosanoid Synthesis LeukotrienesProstaglandins, thromboxanes NSAIDs Cyclo- oxygenase Lipoxygenase Membrane lipids Arachidonic Acid Steroids Phospholipase A2
- 29. Properties Induction of inflammation Mediationof pain signals Induction of fever Smooth muscle contraction (including uterus) Smooth muscle relaxation Protection of stomach lining Simulation of platelet aggregation Inhibition of platelet aggregation Sodium and water retention
- 30. Phosphatidyl choline Arachidonic acid PhospholipaseA2 Ca++ Phosphatidylinositol bisphosphate Phospholipase C 1,2 Diacylglycerol Arachidonic acid Monoacylglycerol DAG lipase Arachidonic acid MAG lipase Arachidonic acid release from membrane lipidsArachidonic acid release from membrane lipids Stimulus
- 31. Pathways for ArachidonicAcid MetabolismPathways for Arachidonic Acid Metabolism Arachidonic acid Cyclo-oxygenase Pathway PGG2 Prostaglandins Thromboxanes lipoxygenase Pathway HPETE Leukotrienes HETE Lipoxins
- 32. Function of PGI2,PGE2, PGD2 ↑ Vasodilation, cAMP ↓ Platelet and leukocyte aggregation, IL1 and IL2, T-cell proliferation, lymphocyte migration PGF2a ↑ Vasoconstriction, Bronchoconstriction, smooth muscle contraction TXA2 ↑ Vasoconstriction, Platelet aggregation, lymphocyte proliferation, bronchoconstriction
- 33. Calcium Systems Regulator ofcell function. Involved in the control of motile/fusion process and can act as a second messenger (IP3/DAG system). A different cellular proteins act to control intracellular Ca+2 levels which comprise: A) gated Ca+2 channels B) Ca+2 Pumps Voltage-gated Ca+2 channel (VGCC): VGCC in the synaptic bulb, which allows for Ca+2 entry which in turn leads to vesicle fusion and neurotransmitter release into the synaptic cleft
- 34. Ligand-gated Ca+2 channels (LGCC): LGCCof the SER and mitochondria which recognize IP3 Furthermore, there are a diversity of 'external' ligand-gated channels which respond to neurotransmitters, and a special channel, the ryanodine channel, which is activated by Ca+2 . The significance of the ryanodine channel is that it allows small changes in Ca+2 concentration to be magnified by release on 'large' intracellular stores. Two types of Ca+2 pumps: Utilize a Na+ gradient to move Ca+2 Use ATP directly
- 35. Calmodulin The intracellular effectsof Ca+2 are exhibit through a different Ca+2 binding proteins: Calmodulin. This small protein binds four Ca+2 ions in a cooperative manner and then interacts with a different proteins to modify their activity.