p.1
Autophagy's Role in Cancer Therapy Resistance
How does autophagy relate to RAF inhibitor resistance in cancer?
Autophagy plays a critical role in the development of RAF inhibitor resistance.
p.8
Therapeutic Strategies Targeting RAF and MEK
What is GPLG0259 currently under clinical study for?
Use in obesity and diabetes as an inhibitor of MK5.
p.3
Signaling Pathways in RAS-Driven Cancers
How is RAS activated?
By extracellular stimuli, primarily through complexes of autophosphorylated growth factor receptors, GRB2, and SOS.
p.7
RAF Kinase and Its Role in Tumorigenesis
What happens after the release of the inhibitory domain from the RAF complex?
The RAF kinase domain readily forms RAF-RAF homo-dimers, leading to kinase activation.
p.5
Clinical Applications of MAPK Pathway Inhibitors
What proteins are phosphorylated and activated by RAF?
MEK1 and MEK2, propagating the MAPK cascade.
p.4
RAS/RAF/MAPK Pathway Overview
What is the function of the G-domain in RAS?
It conveys signals to downstream RAS effectors.
p.2
Autophagy's Role in Cancer Therapy Resistance
How does autophagy relate to RAF inhibitors (RAFi) in cancer cells?
Autophagy may assist cancer cells in evading RAFi, as many RAFi-resistant cells exhibit enhanced autophagic activity.
p.2
RAS/RAF/MAPK Pathway Overview
What is the role of the RAF/MEK/ERK signaling cascade?
It governs crucial cellular processes such as development, differentiation, proliferation, and death.
p.1
Development of RAF Inhibitors and Resistance Mechanisms
What is a significant barrier to effective cancer therapy involving RAF inhibitors?
The development of therapy resistance by cancer cells.
p.1
Next-Generation RAF Inhibitors
What is the significance of RAF dimerization in cancer therapy?
RAF activation requires dimerization, making it a potential target for therapeutic intervention.
p.4
RAF Kinase and Its Role in Tumorigenesis
What role does phosphorylation play in CRAF activation?
Phosphorylation of Ser338, Tyr340, and Tyr341 is crucial for CRAF activation.
p.4
RAS/RAF/MAPK Pathway Overview
What are the four isomers of RAS genes?
KRAS4A, KRAS4B, NRAS, and HRAS.
p.1
Clinical Applications of MAPK Pathway Inhibitors
What challenges have been observed in clinical testing of RAF and MEK inhibitors?
Clinical testing has not demonstrated durable responses and is associated with predictable adverse effects.
p.2
Therapeutic Strategies Targeting RAF and MEK
What treatment strategy is suggested for BRAF and KRAS-mutant cancers?
Inhibiting both autophagy and MAPK pathway activity.
p.2
Next-Generation RAF Inhibitors
What was the first BRAF inhibitor approved by the FDA?
Vemurafenib (Zelboraf) for the treatment of metastatic melanoma.
p.6
RAF Kinase and Its Role in Tumorigenesis
What role does RAS play in RAF activation?
RAS engagement increases phosphorylation of the RAF kinase domain and promotes RAF dimerization.
p.4
RAF Kinase and Its Role in Tumorigenesis
What is the significance of RAS mutations like V12Y32F and V12T35S?
They are incapable of RAF activation but can interact with members of the RHO GTPase family.
p.5
Signaling Pathways in RAS-Driven Cancers
What initiates RAS activation in the RAS/RAF/MAPK pathway?
Binding of various mitogens like TGF-α, EGF, VEGF, and PDGF-β to their receptors.
p.7
RAF Kinase and Its Role in Tumorigenesis
What role does the RAF-related pseudo-kinase KSR play?
It participates in forming side-to-side heterodimers with RAF (RAF-KSR heterodimer).
p.4
RAS/RAF/MAPK Pathway Overview
What posttranslational modifications occur in the C-terminal region of RAS?
Iso-prenylation, proteolysis, and methylation.
p.6
RAF Kinase and Its Role in Tumorigenesis
What happens to RAF proteins in the absence of cellular stimuli?
They exist in a monomeric, autoinhibited, inactive form.
p.7
Mechanisms of Cancer Metastasis
What activates the p38 signaling pathway?
A wide range of environmental stressors and inflammation.
p.4
RAF Kinase and Its Role in Tumorigenesis
How does CRAF interact with MEK?
CRAF forms interactions with MEK, which is responsible for activating ERK.
p.8
Accessory Proteins in MAPK Signaling
What triggers NLK activation?
Wnt pathway stimulation (Wnt-1 and Wnt-5a) and TGF-β.
p.6
RAF Kinase and Its Role in Tumorigenesis
Which proteins are involved in the regulation of CRAF activity?
PAK1, PAK2, PAK3, and other interacting proteins like CK2 and Src.
p.8
Accessory Proteins in MAPK Signaling
What role do docking proteins play in cellular signaling?
They bind to receptors like RTKs and GPCRs, recruiting effector molecules.
p.3
Signaling Pathways in RAS-Driven Cancers
What happens to RAS after GTP hydrolysis?
The signaling from RAS is terminated, and RAS returns to its inactive GDP-bound form.
p.1
RAS/RAF/MAPK Pathway Overview
What is the primary signaling cascade targeted by multi-kinase inhibitors in cancer therapy?
The mitogen-activated protein kinase (MAPK) pathway.
p.6
RAF Kinase and Its Role in Tumorigenesis
What is the role of the N-terminal regulatory domain in RAF proteins?
It contains CR1 and CR2, which are involved in autoinhibition and regulation of RAF activity.
p.1
Therapeutic Strategies Targeting RAF and MEK
What combination therapy may be more effective for advanced RAF-mutant carcinomas?
Combination of RAF and MEK inhibitors.
p.2
Clinical Applications of MAPK Pathway Inhibitors
What are the implications of ongoing studies targeting the RAS/RAF/MAPK pathway?
They aim to develop new treatments for various disorders, including neurological and inflammatory diseases.
p.3
Signaling Pathways in RAS-Driven Cancers
Which growth factors can instigate the RAS-RAF-MEK-ERK pathway?
TGF-α, EGF, VEGF, and PDGF-β.
p.5
RAF Kinase and Its Role in Tumorigenesis
In what form do RAF proteins exist initially?
In the cytoplasm in an inactive monomeric form.
p.8
RAF Kinase and Its Role in Tumorigenesis
What is RKIP and its significance in cancer?
RKIP is a tumor suppressor and intrinsic RAF kinase inhibitor associated with malignant features like metastasis and chemotherapy resistance.
p.2
Signaling Pathways in RAS-Driven Cancers
What is the significance of identifying key downstream signals in the MAPK pathway?
It minimizes paralog redundancy and cascade interactions, which may limit cancerous activity of RAF and drug toxicity in normal cells.
p.1
Therapeutic Strategies Targeting RAF and MEK
What is a potential new therapeutic strategy for RAS-driven cancers?
Interrupting signals between RAS and downstream effectors like the RAF-MEK-ERK pathway.
p.2
Signaling Pathways in RAS-Driven Cancers
What are the four primary MAPKs in mammals?
ERK1/2, c-Jun N-terminal kinase (JNK)1-3, p38, and ERK5.
p.3
Signaling Pathways in RAS-Driven Cancers
What are the two pathways that can activate the RAS/RAF/MAPK pathway?
Ligand-dependent pathway and ligand-independent pathway.
p.8
Accessory Proteins in MAPK Signaling
What are the four categories of MAPK accessory proteins?
Anchoring proteins, docking proteins, adapter proteins, and scaffold proteins.
p.8
Accessory Proteins in MAPK Signaling
How do adapter proteins facilitate signal transduction?
By connecting two functional components and providing additional docking sites.
p.7
Signaling Pathways in RAS-Driven Cancers
What are some of the cellular responses triggered by activated ERK?
Responses include phosphorylation of various cytoplasmic and nuclear substrates, including transcription factors.
p.1
RAF Kinase and Its Role in Tumorigenesis
What role does RAF kinase play in the MAPK pathway?
RAF kinase mediates the sequential activation of downstream targets like MEK and ERK.
p.2
Therapeutic Strategies Targeting RAF and MEK
What was the finding of Chih-Shia Lee's group regarding RAF and autophagy genes?
Targeting both RAF and autophagy genes results in the best therapeutic outcomes.
p.4
RAF Kinase and Its Role in Tumorigenesis
What is required for RAF activation?
Direct interaction between RAS and the N-terminal regulatory domain of CRAF.
p.8
Accessory Proteins in MAPK Signaling
Which transcription factors are targeted by NLK?
T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors and STAT3.
p.6
RAF Kinase and Its Role in Tumorigenesis
What is the function of AKT in relation to BRAF?
AKT physically interacts with BRAF and balances the cross-regulation between PI3K-AKT and RAS-RAF-MEK signaling cascades.
p.7
Signaling Pathways in RAS-Driven Cancers
What is the significance of the phosphorylation of target proteins in the ERK pathway?
It can regulate associated signaling pathways based on the functional location of target proteins.
p.1
RAF Kinase and Its Role in Tumorigenesis
What types of cancers are commonly associated with RAF mutations?
Melanoma, non-small cell lung carcinoma, and thyroid cancer.
p.6
RAF Kinase and Its Role in Tumorigenesis
How does RAF activation occur?
Through the removal of inhibitory enforcement at the RAF catalytic domain.
p.8
Accessory Proteins in MAPK Signaling
What factors are associated with the activation of NLK?
Granulocyte colony-stimulating factor and transforming growth factor-beta (TGF-β).
p.6
RAF Kinase and Its Role in Tumorigenesis
What is the relationship between RAF dimerization and disease-associated mutant RAF?
RAF dimerization is necessary for RAS-dependent RAF kinase activity and correlates with the pathogenic role of mutant RAF.
p.3
RAS/RAF/MAPK Pathway Overview
What is the significance of RAS in the RAF/MAPK pathway?
RAS is a pivotal upstream protein and the founding member of the RAS superfamily of small GTPases.
p.3
Signaling Pathways in RAS-Driven Cancers
What role do GEFs play in RAS activation?
GEFs, like SOS, facilitate the release of GDP from RAS, leading to its activation.
p.7
RAF Kinase and Its Role in Tumorigenesis
How does inhibitory phosphorylation affect RAF dimeric structures?
It can disrupt and inactivate dimeric structures.
p.6
RAF Kinase and Its Role in Tumorigenesis
What is required for maximal activity of ARAF and CRAF?
Phosphorylation of activating residues and dephosphorylation of negative regulatory residues.
p.2
Signaling Pathways in RAS-Driven Cancers
What is the role of ERK in the RAS/RAF/MAPK pathway?
ERK plays a pivotal role in controlling various facets of cellular metabolism in cancer cells.
p.3
RAF Kinase and Its Role in Tumorigenesis
What can contribute to the development of malignancies in humans?
Atypical RAF activation or mutations in upstream activators like RAS or receptor tyrosine kinases (RTKs).
p.5
RAF Kinase and Its Role in Tumorigenesis
Which proteins may be involved in CRAF activation?
CK2, JNK2, or SRC, through either RAS-dependent or RAS-independent mechanisms.
p.5
RAF Kinase and Its Role in Tumorigenesis
What triggers RAF dimerization?
Stimulation by RAS-GTP, which releases the autoinhibitory domain.
p.7
Signaling Pathways in RAS-Driven Cancers
What is the role of ERK5 in cellular processes?
It is involved in cell survival and proliferation, increasing cyclin D1 expression.
p.6
RAF Kinase and Its Role in Tumorigenesis
What is the significance of RAF translocation to the plasma membrane?
It is a vital step for the activation of the RAF kinase domain.
p.8
Accessory Proteins in MAPK Signaling
What is the function of anchoring proteins in MAPK signaling?
They connect and associate with effector proteins, primarily kinases.
p.7
RAF Kinase and Its Role in Tumorigenesis
What structural association is involved in the formation of the side-by-side RAF dimer?
A structural association between the N- and C-terminal regions of the kinase domain.
p.5
Signaling Pathways in RAS-Driven Cancers
What is the role of GEFs in the GTPase cycle?
They stimulate the transition of inactive RAS-GDP to active RAS-GTP.
p.7
Signaling Pathways in RAS-Driven Cancers
Which proteins are phosphorylated by activated RAF kinase?
MEK1 and MEK2, leading to the activation of ERK1 and ERK2.
p.4
Signaling Pathways in RAS-Driven Cancers
What is the role of MAPKKs in the MAPK pathway?
They phosphorylate and activate the terminal serine/threonine MAPK.
p.5
RAS/RAF/MAPK Pathway Overview
What role do p21-activated kinase (PAK) family members play in cell signaling?
They serve as molecular linkers, connecting RAS with RHO GTPases, including RAC and CDC42.
p.5
RAF Kinase and Its Role in Tumorigenesis
What is required for the activation of RAF?
A series of regulatory steps that relieve its autoinhibited state.
p.5
Signaling Pathways in RAS-Driven Cancers
What are the components of the RAS protein structure?
Effector lobe, allosteric lobe, and hypervariable region (HVR).
p.7
Mechanisms of Cancer Metastasis
What is the role of the JNK pathway?
It responds to cytokines, growth factor deprivation, and various stressors.
p.8
Accessory Proteins in MAPK Signaling
What roles do ERK3, ERK7, and NLK play in cellular processes?
Cell proliferation, cell cycle progression, migration, invasion, apoptosis, and cell differentiation.
p.8
Accessory Proteins in MAPK Signaling
What is the role of scaffold proteins in the MAPK pathway?
They offer a signaling platform for the spatial regulation of the MAPK pathway.
p.3
RAF Kinase and Its Role in Tumorigenesis
What are some RAS-related malignancies associated with?
GAPs, including NF1, p120GAP/RASA1, and others.
p.3
RAS/RAF/MAPK Pathway Overview
What historical milestone marked the identification of RAF?
RAF was identified as an upstream kinase activator of MEK and a RAS effector in 1992.
p.7
Signaling Pathways in RAS-Driven Cancers
What activates the ERK5 pathway?
Growth factors, some cytokines, and stressors like osmotic stress.
p.5
RAF Kinase and Its Role in Tumorigenesis
What is the outcome of RAF dimerization?
Mutual phosphorylation of the dimer components, fully activating the kinase.
p.7
Signaling Pathways in RAS-Driven Cancers
What is the function of MEK in the MAPK pathway?
MEK phosphorylates regulatory Tyr and Thr sites to activate ERK.
