RAS-MAPK SIGNALING PATHWAY

The RAS-MAPK signaling pathway is a crucial cellular communication pathway that regulates cell growth, differentiation, and survival. Known for its involvement in cell cycle control, this pathway is often dysregulated in cancer and other diseases. This intricate cascade, involving RAS proteins, RAF kinases, MEK, and MAPK (ERK), transmits signals from surface receptors to the nucleus, impacting gene expression and cell function.

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AnyGenes qPCR arrays provide researchers with a comprehensive toolset for investigating the RAS-MAPK pathway. By enabling precise detection of key gene expression changes, AnyGenes products offer a reliable resource for studying cellular signaling dynamics and the impact of therapeutic interventions on RAS-MAPK-driven pathways.

RAS-MAPK Signaling Pathway Diagram featuring AnyGenes qPCR Array.

Discover our advanced qPCR arrays for RAS-MAPK Signaling Pathway research.

The MAPK cascade illustrating signal transduction pathways involved in cell growth, differentiation, and stress response.

The MAPK cascade. Once a ligand binds the tyrosine kinase receptor, it self-phosphorylates [18]. This creates binding sites for Shc and Shp2. GRB2 can associate with either and then recruit SOS [19,20]. SOS is a guanine exchange factor for Ras and induces the exchange of GDP for GTP [21]. Now active Ras will dimerize and bind Raf [21]. After activating Raf, GTPase activating proteins (GAP) will hydrolyze the GTP to GDP to return Ras to its resting inactive state [22]. The active Raf dimers will recruit MEK [23], which then activates ERK [3]. ERK interacts with Importin 7 at the nuclear envelope to facilitate its entry through the nuclear pore complex into the nucleus [24,25]. Once inside, it phosphorylates multiple transcription factors to alter gene expression in the cell and induce proliferation and survival [26].

KEY MOLECULES IN THE RAS-MAPK SIGNALING PATHWAY

The RAS-MAPK pathway relies on several key proteins that interact to ensure accurate signal transduction.

RAS Proteins: These GTP-binding proteins play an essential role in signal relay, with mutations in RAS genes (e.g., KRAS, NRAS) being linked to various cancers.
RAF Kinases: RAF proteins, including BRAF, are serine/threonine kinases that activate downstream signaling molecules like MEK.
MEK and ERK/MAPK: MEK phosphorylates ERK, which then translocates to the nucleus to alter gene expression, affecting cell division and survival.

BIOLOGICAL FUNCTIONS AND MECHANISMS OF ACTION

The RAS-MAPK pathway plays a vital role in several physiological processes:

Cell Growth and Division: It regulates the cell cycle and promotes proliferation.
Differentiation: It influences cell fate decisions during development.
Survival: The pathway helps cells resist apoptosis under certain conditions.
Angiogenesis: It is involved in the formation of new blood vessels by regulating gene expression related to vascular growth.

RAS-MAPK pathway is initiated when a ligand binds to an RTK, leading to receptor dimerization and autophosphorylation. This creates docking sites for adaptor proteins like GRB2, which recruit GEFs such as SOS1. These GEFs facilitate the exchange of GDP for GTP on RAS, activating it. Activated RAS then interacts with RAF kinases at the plasma membrane, promoting a series of phosphorylation events that propagate the signal through MEK to ERK.

DYSREGULATION OF RAS-MAPK SIGNALING PATHWAY AND DISEASES

Alterations in the RAS-MAPK pathway are commonly observed in cancer, as well as in neurological and developmental disorders known as RASopathies. Mutations can lead to uncontrolled cell proliferation, resistance to apoptosis, and enhanced survival, which are hallmarks of malignancy. For instance, BRAF mutations are frequently found in melanoma and thyroid cancers. Therapeutic targeting of this pathway, especially at the level of MEK and BRAF, has shown promise in treating specific cancers, although resistance mechanisms often emerge.

RECENT ADVANCES

Mechanistic insights into RAF Kinase signaling: Recent reviews have highlighted the complexities of RAF kinase signaling within the RAS-MAPK pathway, particularly its role in tumorigenesis and the mechanisms underlying resistance to RAF inhibitors (RAFi).
Targeting Accessory Proteins: The role of accessory proteins in the RAS-MAPK pathway has gained attention, with new discoveries suggesting that these proteins can modulate signal transduction efficiency and specificity.
Neuroblastoma and RAS-MAPK Activation: Research has shown that mutations affecting the RAS-MAPK pathway are prevalent in relapsed neuroblastoma tumors, correlating with aggressive tumor behavior and poor prognosis.
Broadening Therapeutic Applications: The implications of the RAS-MAPK pathway extend beyond cancer; ongoing studies are exploring its role in various neurological and developmental disorders, such as autism spectrum disorder, Alzheimer's disease, rheumatoid arthritis and inflammatory bowel disease.
Combination Therapies: The future of RAS-MAPK research is leaning towards combination therapies that target multiple points within the pathway or integrate other signaling pathways.

(1) Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther. (2023)18;8(1):455.

(2) Pudewell S, et al. Accessory proteins of the RAS-MAPK pathway: moving from the side line to the front line. Commun Biol. (2021)8;4(1):696.

(3) Dillon M, et al. Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers. Cancers (Basel). (2021)10;13(20):5059.

(4) Santarpia L, Lippman SM, El-Naggar AK. Targeting the Mitogen-Activated Protein Kinase RAS-RAF Signaling Pathway in Cancer Therapy. Expert Opin Ther Targets. (2012);16(1):103-19.

RAS-MAPK SIGNALING PATHWAY BIOMARKER LIST

Customize your own signaling pathways (SignArrays®) with the factors of your choice!
Simply download and complete our Personalized SignArrays® information file and send it at [email protected] to get started on your project.

You can check the biomarker list included in this pathway, see below:

Species : Homo sapiens (human)

Signaling Pathways	Product ref	Informations
RAS-MAPK Signaling Pathway	RAS1H1	List infos

Species : Mus musculus (mouse)

Signaling Pathways	Product ref	Informations
RAS-MAPK Signaling Pathway	*******	List In progress...

Species : Rattus norvegicus (rat)

Signaling Pathways	Product ref	Informations
RAS-MAPK Signaling Pathway	*******	List In progress...

Species : Sus Scrofa (Pig)

Signaling Pathways	Product ref	Informations
RAS-MAPK Signaling Pathway	*******	List In progress...

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