s41392-023-01705-z

Autophagy plays a critical role in the development of RAF inhibitor resistance.

More than 30%.

Use in obesity and diabetes as an inhibitor of MK5.

By extracellular stimuli, primarily through complexes of autophosphorylated growth factor receptors, GRB2, and SOS.

The RAF kinase domain readily forms RAF-RAF homo-dimers, leading to kinase activation.

MEK1 and MEK2, propagating the MAPK cascade.

It conveys signals to downstream RAS effectors.

Autophagy may assist cancer cells in evading RAFi, as many RAFi-resistant cells exhibit enhanced autophagic activity.

It governs crucial cellular processes such as development, differentiation, proliferation, and death.

The development of therapy resistance by cancer cells.

RAF activation requires dimerization, making it a potential target for therapeutic intervention.

Phosphorylation of Ser338, Tyr340, and Tyr341 is crucial for CRAF activation.

KRAS4A, KRAS4B, NRAS, and HRAS.

ARAF, BRAF, and CRAF.

Clinical testing has not demonstrated durable responses and is associated with predictable adverse effects.

Inhibiting both autophagy and MAPK pathway activity.

Vemurafenib (Zelboraf) for the treatment of metastatic melanoma.

RAS engagement increases phosphorylation of the RAF kinase domain and promotes RAF dimerization.

They are incapable of RAF activation but can interact with members of the RHO GTPase family.

Binding of various mitogens like TGF-α, EGF, VEGF, and PDGF-β to their receptors.

It participates in forming side-to-side heterodimers with RAF (RAF-KSR heterodimer).

Iso-prenylation, proteolysis, and methylation.

They exist in a monomeric, autoinhibited, inactive form.

A wide range of environmental stressors and inflammation.

CR1, CR2, and CR3.

CRAF forms interactions with MEK, which is responsible for activating ERK.

Wnt pathway stimulation (Wnt-1 and Wnt-5a) and TGF-β.

PAK1, PAK2, PAK3, and other interacting proteins like CK2 and Src.

They bind to receptors like RTKs and GPCRs, recruiting effector molecules.

The signaling from RAS is terminated, and RAS returns to its inactive GDP-bound form.

The mitogen-activated protein kinase (MAPK) pathway.

It contains CR1 and CR2, which are involved in autoinhibition and regulation of RAF activity.

Combination of RAF and MEK inhibitors.

They aim to develop new treatments for various disorders, including neurological and inflammatory diseases.

TGF-α, EGF, VEGF, and PDGF-β.

In the cytoplasm in an inactive monomeric form.

RKIP is a tumor suppressor and intrinsic RAF kinase inhibitor associated with malignant features like metastasis and chemotherapy resistance.

It minimizes paralog redundancy and cascade interactions, which may limit cancerous activity of RAF and drug toxicity in normal cells.

Interrupting signals between RAS and downstream effectors like the RAF-MEK-ERK pathway.

ERK1/2, c-Jun N-terminal kinase (JNK)1-3, p38, and ERK5.

Ligand-dependent pathway and ligand-independent pathway.

Anchoring proteins, docking proteins, adapter proteins, and scaffold proteins.

By connecting two functional components and providing additional docking sites.

Responses include phosphorylation of various cytoplasmic and nuclear substrates, including transcription factors.

RAF kinase mediates the sequential activation of downstream targets like MEK and ERK.

Targeting both RAF and autophagy genes results in the best therapeutic outcomes.

Direct interaction between RAS and the N-terminal regulatory domain of CRAF.

T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors and STAT3.

AKT physically interacts with BRAF and balances the cross-regulation between PI3K-AKT and RAS-RAF-MEK signaling cascades.

It can regulate associated signaling pathways based on the functional location of target proteins.

Melanoma, non-small cell lung carcinoma, and thyroid cancer.

Through the removal of inhibitory enforcement at the RAF catalytic domain.

Granulocyte colony-stimulating factor and transforming growth factor-beta (TGF-β).

RAF dimerization is necessary for RAS-dependent RAF kinase activity and correlates with the pathogenic role of mutant RAF.

RAS is a pivotal upstream protein and the founding member of the RAS superfamily of small GTPases.

GEFs, like SOS, facilitate the release of GDP from RAS, leading to its activation.

It can disrupt and inactivate dimeric structures.

Phosphorylation of activating residues and dephosphorylation of negative regulatory residues.

ERK plays a pivotal role in controlling various facets of cellular metabolism in cancer cells.

Atypical RAF activation or mutations in upstream activators like RAS or receptor tyrosine kinases (RTKs).

CK2, JNK2, or SRC, through either RAS-dependent or RAS-independent mechanisms.

Stimulation by RAS-GTP, which releases the autoinhibitory domain.

It is involved in cell survival and proliferation, increasing cyclin D1 expression.

It is a vital step for the activation of the RAF kinase domain.

They connect and associate with effector proteins, primarily kinases.

A structural association between the N- and C-terminal regions of the kinase domain.

They stimulate the transition of inactive RAS-GDP to active RAS-GTP.

MEK1 and MEK2, leading to the activation of ERK1 and ERK2.

They phosphorylate and activate the terminal serine/threonine MAPK.

They serve as molecular linkers, connecting RAS with RHO GTPases, including RAC and CDC42.

A series of regulatory steps that relieve its autoinhibited state.

Effector lobe, allosteric lobe, and hypervariable region (HVR).

It responds to cytokines, growth factor deprivation, and various stressors.

Cell proliferation, cell cycle progression, migration, invasion, apoptosis, and cell differentiation.

Approximately 30%.

They offer a signaling platform for the spatial regulation of the MAPK pathway.

GAPs, including NF1, p120GAP/RASA1, and others.

RAF was identified as an upstream kinase activator of MEK and a RAS effector in 1992.

Growth factors, some cytokines, and stressors like osmotic stress.

Mutual phosphorylation of the dimer components, fully activating the kinase.

MEK phosphorylates regulatory Tyr and Thr sites to activate ERK.