MAPK/Erk Growth and Differentiation Pathway

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.

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.

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.