Boster Pathways-> Kinase Signaling

MAPK/Erk Growth and Differentiation Pathway

The MAPK/Erk signaling cascade is triggered by a diverse array of growth and differentiation-related receptors, including receptor tyrosine kinases (RTKs), integrins, and ion channels.

Overview of The MAPK-ERK Signaling Pathway: What Is It?

MAPKs are a highly conserved signaling pathway found in both lower prokaryotic and higher mammalian cells. The signaling pathway is capable of transducing extracellular stimulation signals into cells and their nuclei, resulting in a cascade of biological events such as cell proliferation, differentiation, transformation, and apoptosis.

Pathway's Function

This signaling pathway is primarily responsible for regulating cell proliferation, transformation, differentiation, and apoptosis. Numerous hormones, growth and differentiation factors, and tumor-promoting substances activate this signaling pathway.

The MAPK-ERK Signaling Pathway in Action

Tyrosine kinases in receptors, G-protein-coupled receptors, and/or integrins initiate this signaling pathway by activating small GTPases Ras (and possibly Rap). By inducing the exchange of Ras-bound GDP for GTP, these membrane proteins recruit and activate Ras proteins. And Ras inactivation is regulated by GAPs (GTPase - activation proteins), which enhance Ras GTPase activity by promoting GDP hydrolysis to GTP. When activated, the small G protein recruits and activates MKKKs c-Raf (A-Raf and B-Raf) to the plasma membrane. By phosphorylating serine residues, activated Raf activates MEK-1/2. MEK-1/2 activates ERK-1/2 by phosphorylating the protein's threonine and tyrosine residues.

Activated ERK can phosphorylate several nuclear transcription factors, including c-fos, c-Jun, Elk-1, c-myc, and ATF2, which play a direct role in cell proliferation and differentiation regulation. Additionally, it targets indirect gene regulation via substrates such as p90-RSK (ribosomal S6 kinase). Additionally, ERK can act as a negative feedback regulator by phosphorylating upstream ERK pathway proteins such as the NGF receptor, SOS, Raf-1, and MEK.

Additionally, other studies have demonstrated that ERKs phosphorylates cytoskeletal components in the cytoplasm, such as tubule-associated proteins MAP-1, MAP-2, and MAP-4, thereby regulating cell morphology and cytoskeleton redistribution.

Cancer and the MAPK-ERK Signaling Pathwayay

Cancer develops when genetic and epigenetic changes disrupt the body's normal regulatory mechanism. Numerous critical signaling cascades, such as the MAPK-ERK pathway, are altered in cancer. Mutations in the signaling pathway's RAS/RAF/MEK/ERK genes are found in the majority of solid tumors. RAS mutants encode mutated proteins that are GAP-insensitive and constitutively GTP-bound, resulting in ERK1/2 activation that is stimulus-independent and sustained. Oncogenic BRAF mutations result in an increase in the activity of MEK and ERK1/2, which are downstream effectors of BRAF. Additionally, abnormal tyrosine kinase receptor activation has been observed in a variety of human cancers. All of the upstream mutations can result in increased ERK protein activity, which further phosphorylates and activates a series of ERK-regulated substrates, including CREB (cAMP response element-binding protein), c-Myc (transcriptional regulator Myc-like), NF-B (nuclear factor kappa B), AP-1, and members of the signal transducer and activator of transcription family. The functional consequences of ERK1/2 phosphorylation at the substrate level include changes in cellular motility and gene expression, which promote tumor cell proliferation, differentiation, migration, and angiogenesis.

Additionally, overexpression of ERK1/2 regulates anti-apoptotic molecules such as BCL-2, inhibiting tumor apoptosis. Given the close association between aberrant activation of the MAPK-ERK pathway and a variety of different types of cancer, manipulating this pathway and its downstream molecules represents an exciting therapeutic target for cancer treatment.