FUNCTION Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126). Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.CATALYTIC ACTIVITY L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+)ACTIVITY REGULATION Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2 (PubMed:29433126). Activation occurs through phosphorylation of Ser-218 and Ser-222 (By similarity). MAP2K1/MEK1 binds KSR1 or KSR2 releasing the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains (PubMed:29433126). This allows KSR1 or KSR2 dimerization with BRAF leading to BRAF activation and phosphorylation of MAP2K1 (PubMed:29433126). MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A (By similarity). Many inhibitors have been identified including pyrrole derivatives, TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives), CH4987655 and RDEA119/BAY 869766 (PubMed:15543157, PubMed:17880056, PubMed:18951019, PubMed:19019675, PubMed:19161339, PubMed:19706763, PubMed:20621728, PubMed:21310613).SUBUNIT Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14 (By similarity). Forms a heterodimer with MAP2K2/MEK2 (By similarity). Forms heterodimers with KSR2 which further dimerize to form tetramers (By similarity). Interacts with KSR1 or KSR2 and BRAF; the interaction with KSR1 or KSR2 mediates KSR1-BRAF or KSR2-BRAF dimerization (PubMed:10409742, PubMed:29433126). Interacts with ARBB2, LAMTOR3 and RAF1 (By similarity). Interacts with MAPK1/ERK2 (PubMed:32721402). Interacts with MORG1 (By similarity). Interacts with PPARG (PubMed:17101779). Interacts with isoform 1 of VRK2 (PubMed:20679487). Interacts with SGK1 (PubMed:19447520). Interacts with BIRC6/bruce (PubMed:18329369). Interacts with KAT7; the interaction promotes KAT7 phosphorylation (By similarity). Interacts with RAF1 and NEK10; the interaction is required for ERK1/2-signaling pathway activation in response to UV irradiation (PubMed:20956560). Interacts with TRAF3IP3 (PubMed:26195727). Interacts with MOS (PubMed:34779126, PubMed:35670744).SUBUNIT (Microbial infection) Interacts with Yersinia YopJ.INTERACTION Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis (PubMed:14737111). Membrane localization is probably regulated by its interaction with KSR1 (PubMed:10409742).ALTERNATIVE PRODUCTS Widely expressed, with extremely low levels in brain.DOMAIN The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1.PTM Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (BRAF or MEKK1) positively regulates kinase activity (PubMed:29433126, PubMed:8131746). Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK (PubMed:16129686). MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK (PubMed:16129686). Autophosphorylated at Ser-218 and Ser-222, autophosphosphorylation is promoted by NEK10 following UV irradiation (PubMed:20956560).PTM (Microbial infection) Acetylation by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.