Map2k1

What is MAP2K1 protein?

The protein encoded by MAP2K1 gene is a member of the dual specificity protein kinase family that acts as a mitogen-activated protein (MAP) kinase kinase. 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. Depending on the cellular context, this kinase is involved in diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. 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.

MAP2K1 related signaling pathway

The RAS-MAPK pathway: The RAS-MAPK pathway is a signal transduction cascade that plays a crucial role in normal cellular processes such as cell growth, proliferation, differentiation, survival, metabolism and migration. The pathway is stimulated by growth factors that lead to RAS-mediated RAF activation. This kinase phosphorylates MEK1 and/or MEK2 with consequent ERK1/2 activation, downstream the cascade. ERK1 and ERK2 effectors act both in nucleus and in cytoplasm, mediating the polymorphic cellular response to growth factors.

The ERK-MAPK pathway: Extensive studies have demonstrated the importance of the ERK-MAPK pathway in promoting early commitment and differentiation of skeletal progenitors to the osteoblast lineage and skeletal mineralization.

The mTOR pathway: The ERK-MAPK pathway controls the mTOR pathway, a signaling modulator of mitochondrial biogenesis that regulates cellular energy metabolism. ERK inhibition by an MEK inhibitor activates the mTORC2-AKT signaling axis downstream of epidermal growth factor.

The Hippo pathway: The findings show that MEK1 promotes YAP protein expression through beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC). Dysfunctional Hippo/YAP signaling pathway has been linked to hepatocarcinogenesis. Further research found that YAP and MEK1 were closely correlated in tumor samples.

MAP2K1 Related Diseases

Cardiofaciocutaneous syndrome 3 (CFC3) : It is an autosomal dominant syndrome, caused by heterozygous pathogenic variants in the genes BRAF, MAP2K1/MEK1, MAP2K2/MEK2, KRAS or, rarely, YWHAZ, all part of the RAS-MAPK pathway. A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability.

Melorheostosis, isolated (MEL): MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. A sclerosing bone disorder characterized by hyperostosis of the cortex of tubular bones, frequently involving one limb.

Other malignant disease: MAP2K1 is invlved in diverse pathways, once any related pathway anomalies, it can cause diseases of varying degrees like histiocytosis in Langerhans cell, tumorigenesis in liver cancer and melanoma so on.

Fig1. Mutations of MAP2K1 in histiocytoses. Description of all mutation detected, corresponding to either (A) SBSs or (B) DELINs. Correlation of the type of genetic alteration with age and subtype of histiocytosis. C1: SBSs and C2: DELINs.