Map3k1

Fig1. Pathogenic variants in MAP3K1(shown above the diagram) occur in or near known functional domains. (Harry Ostrer, 2022)

What is MAP3K1 Protein?

MAP3K1 gene (mitogen-activated protein kinase kinase kinase 1) is a protein coding gene which situated on the long arm of chromosome 5 at locus 5q11. The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. The MAP3K1 protein is consisted of 1512 amino acids and MAP3K1 molecular weight is approximately 164.5 kDa.

What is the Function of MAP3K1 Protein?

MAP3K1 protein is a serine/threonine kinase that plays an important role in cell signaling. MAP3K1 is involved in regulating a variety of biological processes, including cell proliferation, differentiation, migration, and apoptosis, through activation of downstream ERK and JNK signaling pathways, as well as the NF-κB pathway. The full-length form of MAP3K1 regulates cell migration and promotes cell survival signaling, while its cleavage mediated by caspase 3 produces a C-terminal kinase domain that promotes apoptosis. In terms of antiviral immunity, MAP3K1 regulates the production of type I interferon (IFN-I) by activating MAP2K1/4/7, which is essential for the cell's defense against viruses. The expression and activity of MAP3K1 are regulated by multiple mechanisms, including transcriptional regulation, allosteric regulation, and post-translational modification.

MAP3K1 Related Signaling Pathway

MAP3K1 activates extracellular signal-regulated kinase (ERK), a major branch of the MAPK signaling pathway involved in cell proliferation, differentiation, and apoptosis. JNK (c-Jun N-terminal kinase) signaling pathway is associated with inflammation, stress response and apoptosis. MAP3K1 may activate JNK through its downstream kinase MAP2K4/7, thereby affecting the stress response of cells. p38 kinase pathway is involved in the regulation of inflammatory response, cell cycle progression and apoptosis. MAP3K1 may activate p38 MAPK by activating MAP2K3/6, which is involved in cell response to various stress signals. MAP3K1 is involved in activating the NF-κB signaling pathway, which plays a central role in controlling cell survival, inflammation, and immune response. MAP3K1 may play a role in toll-like receptor mediated signaling pathway, which is involved in regulating host immune response to pathogens.

MAP3K1 Related Diseases

Mutations in the MAP3K1 gene, or dysregulation of its signaling pathway, have been linked to a variety of diseases, particularly cancer, such as breast, ovarian, and lung cancer, as it plays a key role in regulating cell proliferation and survival. In addition, abnormal functioning of MAP3K1 is also associated with inflammatory diseases, as it is involved in the activation of inflammatory signaling pathways. In neurodegenerative diseases, MAP3K1 signaling may also be affected, affecting cellular stress responses and cell death. Therefore, MAP3K1 is the focus of research in many pathological conditions, and interventions targeting its signaling pathway may provide new strategies for treating related diseases.

Bioapplications of MAP3K1

MAP3K1 has become an important target for drug development, especially in the field of cancer therapy, due to its important role in cell proliferation, survival, and inflammatory response. Currently, inhibitors targeting MAP3K1 or its downstream signaling pathway members are being researched and developed with the aim of inhibiting tumor growth and metastasis by blocking these signaling pathways. While there are currently no drugs that directly target MAP3K1 in widespread clinical use, there are drugs such as MEK inhibitors (such as Smetinib trametinib) and BRAF inhibitors (such as Verofenib vemurafenib) that treat specific cancers by affecting signaling pathways downstream of MAP3K1. Melanoma with BRAF mutations. The application of these drugs demonstrates the potential to treat disease by targeting MAP3K1-related signaling pathways.

Case Study 1: Wen-Qiao Zang, 2015

To investigate the underlying molecular mechanisms of miR-451 to inhibit proliferation of esophageal carcinoma cell line EC9706. Assays for cell growth, apoptosis and invasion were used to evaluate the effects of miR-451 expression on EC cells. Luciferase reporter and Western blot assays were used to test whether cyclin-dependent kinase inhibitor 2D (CDKN2D) and MAP3K1 act as major targets of miR-451. The results showed that CDKN2D and MAP3K1 are direct targets of miR-451. CDKN2D and MAP3K1 overexpression reversed the effect of miR-451. MiR-451 inhibited the proliferation of EC9706 by targeting CDKN2D and MAP3K1.

Fig1. Western blot analysis of MAP3K1 expression in transfected cells.

Fig2. MAP3K1 silencing and miR-451 overexpression inhibited the cell proliferation.

Case Study 2: Wei Hu, 2020

LncRNAs play crucial roles in the development of various cancers including hepatocellular carcinoma (HCC). Nevertheless, the function of the long noncoding RNA (lncRNA) FOXD2-AS1 in HCC is still poorly understood. This study focused on the role of FOXD2-AS1 in HCC. Researchers demonstrated that miR-206 expression was greatly reduced in HCC cells. Furthermore, the inhibition of FOXD2-AS1 repressed HCC cell proliferation, enhanced cell apoptosis, and restrained cell invasion and migration. MAP kinase 1 (MAP3K1) was predicted to be a target of miR-206. Also, FOXD2-AS1 modulated MAP3K1 expression by sponging miR-206 in MHCC-97L and HepG2 cells. Finally, the in vivo experiments validated that the knockdown of FOXD2-AS1 inhibited HCC progression by modulating the miR-206/MAP3K1 axis.

Fig3. Expression of MAP3K1 protein was detected in HCC cells.

Fig4. Expression of MAP3K1 mRNA was detected in mouse tumor tissues.

Map3k1 has several biochemical functions, for example, ATP binding,JUN kinase kinase kinase activity,MAP kinase kinase kinase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by Map3k1 itself. We selected most functions Map3k1 had, and list some proteins which have the same functions with Map3k1. You can find most of the proteins on our site.

Map3k1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with Map3k1 here. Most of them are supplied by our site. Hope this information will be useful for your research of Map3k1.

DCAF7;YWHAE;BRAF;MAP2K4;HSPA1L;TRAF2;ARRB2