MAPK Signaling Pathways in Apoptosis Notes

MAPK Signaling Pathways in Apoptosis
Introduction
  • MAPK (mitogen-activated protein kinase) signaling pathways regulate biological processes.
  • MAPKs can activate or inhibit apoptosis depending on cell context.
  • Discusses pro- and anti-apoptotic mechanisms regulated by MAPKs, signaling properties, and positive feedback loops.
  • MAPKs’ behavior can be predicted based on stimulus intensity and duration.
  • Highlights the multiple positive feedback loops in apoptosis.
MAPK Cascades
  • MAPK family is activated by dual phosphorylation on a tripeptide motif (Thr-X-Tyr).
  • Activation occurs through a three-tiered cascade: MAPK, MAPKK, and MAPKKK.
  • MAPK inactivation is mediated by phosphatases via dephosphorylation.
  • Scaffold proteins monitor activation and inactivation.
  • Mammals have 14 MAPK members in 7 subgroups; 4 conventional and 3 atypical.
  • MAPKs convert extracellular stimuli into cellular responses like growth, migration, proliferation, differentiation, and apoptosis.
JNK and p38 MAPK Cascades in Pro-Apoptotic Processes
  • JNKs and p38 MAPKs balance cell survival and death from stresses.
  • These kinases integrate signals, converging on caspase activation in a cell-specific manner.
  • Caspases are activated by extrinsic or intrinsic pathways.
  • Cytochrome c release is critical in the intrinsic pathway and is mediated by pro-apoptotic Bcl-2 proteins.
  • Several Bcl-2 family proteins are under JNK and/or p38 MAPK control at transcriptional/post-transcriptional levels.
  • Different JNK and p38 genes exist in vertebrates, but focus is on JNK1-1 and JNK1-2 in osmostress-induced apoptosis.
Transcriptional Regulation
  • JNK and p38 MAPK substrates promote apoptosis.
  • Transcription factors are regulated, increasing pro-apoptotic and decreasing anti-apoptotic protein expression.
  • A major JNK target is AP-1, regulating cell proliferation, differentiation, survival, and apoptosis context-dependently.
  • p53 tumor suppressor is regulated by JNK and p38 MAPK cascades in apoptosis.
  • JNK-mediated phosphorylation stabilizes and activates p53, promoting programmed cell death.
  • p53-p73 dimerization induces apoptotic cell death, particularly in response to JNK-mediated stress.
Post-Transcriptional Modifications
  • JNK/p38 MAPK cascades regulate apoptotic proteins directly in both pathways.
  • The extrinsic pathway induces caspase-8 activation, and in some cells, caspase-8 cleaves Bid, inducing cytochrome c release.
  • The extrinsic and intrinsic pathways converge in the mitochondria.
  • JNK phosphorylates iTCH, promoting degradation of c-FLIP.
  • p38 and JNK regulate autophagy programs, with RIPK and JNK activation inducing autophagic cell death.
  • JNK-mediated phosphorylation of 14-3-3 protein induces Bax release.
  • JNK and p38 directly phosphorylate and regulate Bcl-2 family members, such as Bad, Bax, Bim, and Bmf.
JNK and p38 MAPK Cascades in Anti-Apoptotic Processes
Transcriptional Regulation examples:
  • BNIP3 upregulation protects keratinocytes from UVB-induced apoptosis via ERK and JNK pathways.
  • JNK activation attenuates ER-induced cell death by enhancing anti-apoptotic protein expression.
  • TRPV6 expression via JNK protects hESC-CMs from apoptotic cell death.
  • JNK/c-Jun signaling promotes annexin A2 overexpression, suppressing p53 expression.
  • p38 MAPK induces Nur77 expression, enhancing cell survival via apoptosis suppression.
Post-Translational Regulation examples:
  • Phosphorylation of caspase-9 at Thr125 by ERK1/2 restrains intrinsic apoptosis, with p38 MAPK catalyzing the phosphorylation during hyperosmotic stress.
  • Transient JNK activation delays caspase-9 activation by direct interaction with Apaf 1 and cytochrome c.
  • p38 MAPK/MK2 interacts with RIPK1, inhibiting RIPK1 auto-phosphorylation.
MAPK Signal Cross-Talks
  • Crosstalk between JNK and p38 MAPK regulates stress responses.
  • Pathways share upstream regulators, but p38 MAPK can negatively regulate JNK activity.
  • Balance between JNK and p38 signaling determines cell fate.
  • UV-C-induced p38 activation increases DUSP1 levels, protecting cells from UV-C-induced apoptosis by inactivating JNK.
The Two Faces of ERK in Apoptosis
  • ERK1/2 activation is widely associated with anti-apoptotic functions.
  • ERK can be anti-apoptotic by downregulating pro-apoptotic proteins and upregulating anti-apoptotic proteins.
  • ERK1/2 signaling can be pro-apoptotic; cell cycle arrest and re-entry can induce apoptosis.
  • ERK1/2 interacts with p53 and induces its phosphorylation, a mechanism of DNA damage-induced apoptosis.
  • ERK1/2 activation contributes to the anti-proliferation and apoptotic effects of NSC 95397 in colon cancer cells.
An Easy Guide to Understand MAPKs-Regulated Apoptosis
  • MAPKs must have signaling properties suited for determining cell survival/death.
Basic Signaling Properties of MAPKs
  • MAPKs regulate cell fate decisions.
  • Cellular sensors need properties for irreversible processes: Ultrasensitivity, Hysteresis, Digital Response.
  • Positive and negative feedback loops are common regulatory elements.
  • Ultrasensitive systems in positive feedback loops exhibit bistable behavior.
Strong Versus Weak and Sustained Versus Transient Signaling
  • Ultrasensitive properties and threshold levels explain digital outputs obtained after activation.
  • Strength and duration of signal regulate apoptosis.
  • Transient JNK activation promotes survival, while prolonged JNK activation induces apoptosis.
  • Duration of p38 phosphorylation is crucial; sustained activation is associated with apoptosis, transient with survival.
Feedback Loops
  • Feedback loops are important to regulate intercellular signaling.
  • Negative feedback loops maintain homeostasis and can produce oscillations.
  • Positive feedback loops amplify signals and can create bistable switches.
How Cells Die through Positive Feedback Loops
  • Ultrasensitive response and sustained activation result from positive feedback loops.
  • Multiple positive feedback loops occur during cell death.
  • Cytochrome c release induces caspase-9, promoting release and caspase-9/-3 activation.
  • MEKK1 is cleaved by caspase-3, promoting caspase-9 activation.
  • ROS regulates MAPK activation in a positive circuit.
Xenopus Oocytes as a Cell Model to Understand Apoptosis
  • Xenopus oocytes are valuable for studying cell death mechanisms.
  • They initiate the mitochondrial pathway of apoptosis.
  • Unfertilized Xenopus eggs turn on the apoptotic machinery during meiotic maturation.
  • Cytochrome c microinjection induces caspase-3 activity.
  • Positive feedback loops allow apoptosis to spread in trigger waves.
MAPK Dynamics in Hyperosmotic Shock-Induced Apoptosis
  • Hyperosmolarity damages cells, but cells adapt through survival mechanisms.
  • Hyperosmotic stress induces cytochrome c release and caspase-3 activation.
  • Simultaneous inhibition of p38 and JNK reduces osmostress-induced apoptosis.
  • Caspases induce proteolysis of calpastatin, increasing calpain activation.
  • A model for osmostress-induced apoptosis in Xenopus oocytes presents reversible and irreversible phases.
Concluding Remarks
  • MAPKs regulate apoptosis through transcriptional and post-transcriptional mechanisms.
  • p38 and JNK are usually pro-apoptotic, and ERK is anti-apoptotic, but there are exceptions.
  • MAPK signal crosstalk between JNK and p38 MAPK is an additional regulatory mechanism.
  • The dual role of MAPKs is explained by diverse targets activated