MAP3K4 and Associated Diseases
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Backgrounds of MAP3K4
MAP3K4 is located at chromosome region 6q26, also known as MEKK4, MTK1, and encodes a mitogen-activated protein kinase kinase kinase 4 (MAP3K4) that is a member of the mitogen-activated protein kinase superfamily. MAP3K4 is an important member of the MAPK signaling pathway. MAPK signaling pathway, consisting of a cluster of protein kinase, plays a crucial role in controlling an abroad of biological activities, including cell proliferation, cell motility, cell survival and death, and gene expression. MAP3K4 acts as a mediator in the environmental stress-induced activation of the p38 and JNK signaling to regulate cell proliferation, apoptosis, and migration. MAP3K4 or MEKK4 has been suggested to be important to control the inflammation in Crohn’s Disease (CD), because of its signaling role in NOD2 activation, which is affected by the CD disease-associated NOD2 variants. The MAP3K4 genes have been reported to be associated with a variety of cancers, including PanC.
Functions of MAP3K4
MAP3K4 shows different cellular functions in different cell types, depending on the interconnectivity of different substrates of MAP3K4 and MAPK regulatory pathways. MAP3K4 plays a crucial role in the basic pathology of various neurological diseases. It also plays a critical role in the IGF1R/IR and Akt signaling pathways in TS cells and the placenta and regulates the stem cell epithelial-to-mesenchymal transition (EMT), cell migration, and several inflammatory mediators including IL-6, IL-1β, and COX2. It might be involved in the development of CD by influencing autophagy through the activation of MAPK14 and inhibition of ATG5.
Fig.1 A model of regulatory mechanisms of MAPK signaling in autophagy. (Höcker, 2013)
MAP3K4 and Associated Diseases
A low expression of MAP3K4 and a high expression of its inhibitor GSK3beta may contribute to the LPS unresponsiveness in CD. MAP3K4 knockdown greatly decreased lipid droplet (LDs) formation by reducing JNK activation and subsequent cPLA2 phosphorylation at Ser-505. In addition, because MAP3K4 controls the insulin-like growth factor 1 receptor, stem cells that lack MAP3K4 kinase activity are less sensitive to insulin stimulation. Also, MAP3K4 deficiency in intrahepatic cholangiocarcinoma is the cause of invasive growth. MAP3K4 deficiency results in an overall increase in flamin-A (Fln-A), an actin-binding protein that is essential for cytoskeletal rearrangement and cell locomotion, and increased Fln-A induced by MAP3K4 mutations may impair neuronal migration. Therefore, MAP3K4 may be involved in regulating Fln-A expression and neuronal migration. The elevated expression of MAP3K4 causes abnormal accumulation in nonalcoholic fatty liver disease (NAFLD) by activating JNK and cPLA2. The MAP3K4-JNK-cPLA2 pathway may play a crucial role in the lipogenesis of NAFLD. Overexpression of MAP3K4 reversed the negative effect of miR-183 on neuroinflammation, which resulted in the adversity of neuropathic pain.
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Reference
- Höcker, R.; et al. Inhibition of autophagy through MAPK14-mediated phosphorylation of ATG5. Autophagy. 2013, 9(3): 426-428.
