How does autophagy relate to RAF inhibitor resistance in cancer?
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Autophagy plays a critical role in the development of RAF inhibitor resistance.
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How does autophagy relate to RAF inhibitor resistance in cancer?
Autophagy plays a critical role in the development of RAF inhibitor resistance.
What percentage of human malignancies have RAS mutations that cause constitutive RAF activation?
More than 30%.
What is GPLG0259 currently under clinical study for?
Use in obesity and diabetes as an inhibitor of MK5.
How is RAS activated?
By extracellular stimuli, primarily through complexes of autophosphorylated growth factor receptors, GRB2, and SOS.
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.
What proteins are phosphorylated and activated by RAF?
MEK1 and MEK2, propagating the MAPK cascade.
What is the function of the G-domain in RAS?
It conveys signals to downstream RAS effectors.
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.
What is the role of the RAF/MEK/ERK signaling cascade?
It governs crucial cellular processes such as development, differentiation, proliferation, and death.
What is a significant barrier to effective cancer therapy involving RAF inhibitors?
The development of therapy resistance by cancer cells.
What is the significance of RAF dimerization in cancer therapy?
RAF activation requires dimerization, making it a potential target for therapeutic intervention.
What role does phosphorylation play in CRAF activation?
Phosphorylation of Ser338, Tyr340, and Tyr341 is crucial for CRAF activation.
What are the four isomers of RAS genes?
KRAS4A, KRAS4B, NRAS, and HRAS.
What are the three distinct RAF proteins in mammalian cells?
ARAF, BRAF, and CRAF.
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.
What treatment strategy is suggested for BRAF and KRAS-mutant cancers?
Inhibiting both autophagy and MAPK pathway activity.
What was the first BRAF inhibitor approved by the FDA?
Vemurafenib (Zelboraf) for the treatment of metastatic melanoma.
What role does RAS play in RAF activation?
RAS engagement increases phosphorylation of the RAF kinase domain and promotes RAF dimerization.
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.
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.
What role does the RAF-related pseudo-kinase KSR play?
It participates in forming side-to-side heterodimers with RAF (RAF-KSR heterodimer).
What posttranslational modifications occur in the C-terminal region of RAS?
Iso-prenylation, proteolysis, and methylation.
What happens to RAF proteins in the absence of cellular stimuli?
They exist in a monomeric, autoinhibited, inactive form.
What activates the p38 signaling pathway?
A wide range of environmental stressors and inflammation.
What are the three conserved regions found in all RAF family members?
CR1, CR2, and CR3.
How does CRAF interact with MEK?
CRAF forms interactions with MEK, which is responsible for activating ERK.
What triggers NLK activation?
Wnt pathway stimulation (Wnt-1 and Wnt-5a) and TGF-β.
Which proteins are involved in the regulation of CRAF activity?
PAK1, PAK2, PAK3, and other interacting proteins like CK2 and Src.
What role do docking proteins play in cellular signaling?
They bind to receptors like RTKs and GPCRs, recruiting effector molecules.
What happens to RAS after GTP hydrolysis?
The signaling from RAS is terminated, and RAS returns to its inactive GDP-bound form.
What is the primary signaling cascade targeted by multi-kinase inhibitors in cancer therapy?
The mitogen-activated protein kinase (MAPK) pathway.
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.
What combination therapy may be more effective for advanced RAF-mutant carcinomas?
Combination of RAF and MEK 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.
Which growth factors can instigate the RAS-RAF-MEK-ERK pathway?
TGF-α, EGF, VEGF, and PDGF-β.
In what form do RAF proteins exist initially?
In the cytoplasm in an inactive monomeric form.
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.
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.
What is a potential new therapeutic strategy for RAS-driven cancers?
Interrupting signals between RAS and downstream effectors like the RAF-MEK-ERK pathway.
What are the four primary MAPKs in mammals?
ERK1/2, c-Jun N-terminal kinase (JNK)1-3, p38, and ERK5.
What are the two pathways that can activate the RAS/RAF/MAPK pathway?
Ligand-dependent pathway and ligand-independent pathway.
What are the four categories of MAPK accessory proteins?
Anchoring proteins, docking proteins, adapter proteins, and scaffold proteins.
How do adapter proteins facilitate signal transduction?
By connecting two functional components and providing additional docking sites.
What are some of the cellular responses triggered by activated ERK?
Responses include phosphorylation of various cytoplasmic and nuclear substrates, including transcription factors.
What role does RAF kinase play in the MAPK pathway?
RAF kinase mediates the sequential activation of downstream targets like MEK and ERK.
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.
What is required for RAF activation?
Direct interaction between RAS and the N-terminal regulatory domain of CRAF.
Which transcription factors are targeted by NLK?
T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors and STAT3.
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.
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.
What types of cancers are commonly associated with RAF mutations?
Melanoma, non-small cell lung carcinoma, and thyroid cancer.
How does RAF activation occur?
Through the removal of inhibitory enforcement at the RAF catalytic domain.
What factors are associated with the activation of NLK?
Granulocyte colony-stimulating factor and transforming growth factor-beta (TGF-β).
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.
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.
What role do GEFs play in RAS activation?
GEFs, like SOS, facilitate the release of GDP from RAS, leading to its activation.
How does inhibitory phosphorylation affect RAF dimeric structures?
It can disrupt and inactivate dimeric structures.
What is required for maximal activity of ARAF and CRAF?
Phosphorylation of activating residues and dephosphorylation of negative regulatory residues.
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.
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).
Which proteins may be involved in CRAF activation?
CK2, JNK2, or SRC, through either RAS-dependent or RAS-independent mechanisms.
What triggers RAF dimerization?
Stimulation by RAS-GTP, which releases the autoinhibitory domain.
What is the role of ERK5 in cellular processes?
It is involved in cell survival and proliferation, increasing cyclin D1 expression.
What is the significance of RAF translocation to the plasma membrane?
It is a vital step for the activation of the RAF kinase domain.
What is the function of anchoring proteins in MAPK signaling?
They connect and associate with effector proteins, primarily kinases.
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.
What is the role of GEFs in the GTPase cycle?
They stimulate the transition of inactive RAS-GDP to active RAS-GTP.
Which proteins are phosphorylated by activated RAF kinase?
MEK1 and MEK2, leading to the activation of ERK1 and ERK2.
What is the role of MAPKKs in the MAPK pathway?
They phosphorylate and activate the terminal serine/threonine MAPK.
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.
What is required for the activation of RAF?
A series of regulatory steps that relieve its autoinhibited state.
What are the components of the RAS protein structure?
Effector lobe, allosteric lobe, and hypervariable region (HVR).
What is the role of the JNK pathway?
It responds to cytokines, growth factor deprivation, and various stressors.
What roles do ERK3, ERK7, and NLK play in cellular processes?
Cell proliferation, cell cycle progression, migration, invasion, apoptosis, and cell differentiation.
What percentage of all tumors have RAS mutations?
Approximately 30%.
What is the role of scaffold proteins in the MAPK pathway?
They offer a signaling platform for the spatial regulation of the MAPK pathway.
What are some RAS-related malignancies associated with?
GAPs, including NF1, p120GAP/RASA1, and others.
What historical milestone marked the identification of RAF?
RAF was identified as an upstream kinase activator of MEK and a RAS effector in 1992.
What activates the ERK5 pathway?
Growth factors, some cytokines, and stressors like osmotic stress.
What is the outcome of RAF dimerization?
Mutual phosphorylation of the dimer components, fully activating the kinase.
What is the function of MEK in the MAPK pathway?
MEK phosphorylates regulatory Tyr and Thr sites to activate ERK.