MAP4K4

Official Full Name

mitogen-activated protein kinase kinase kinase kinase 4

Organism

Homo sapiens

GeneID

9448

Background

The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Synonyms

HGK; NIK; MEKKK4; FLH21957; HEL-S-31;

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Detailed Information

Mitogen-activated protein kinase kinase kinase 4 (MAP4K4) belongs to the upstream kinase of the mitogen-activated protein kinase (MAPK) signaling system. The STE20/MAP4K family is an upstream kinase of MAPKKK, and the mammalian STE20/MAP4K family consists of 28 serine/threonine kinases associated with its catalytic domain. The study found that MAP4K4 is highly expressed in a variety of tumor cells. It can accelerate cell transformation, promote cell invasion and reduce adhesion to tissue culture cells, and affect tumor prognosis. MAP4K4 belongs to the GGF IV group and has been found to regulate cell motility, cell rearrangement, and cell proliferation.

Correlation Between MAP4K4 and Tumor

Overexpression of MAP4K4 in tumors suggests that it plays an important role in tumorigenesis. Based on homology to other related kinases, threonine 187 and threonine 191 in the MAP4K4 activation loop are predicted to be potential regulatory phosphorylation sites. By detecting the expression of the MAP4K4 mutant in RIE-1 cells, it was found that MAP4K4 has an effect on cell growth, morphogenesis and invasiveness in matrigel. Three-dimensional invasion and tubule formation experiments were performed to detect the suspension growth of cells in matrigel with and without hepatocyte growth factor (HGF). Studies have shown that in renal epithelial cells, HGF plays an important role in the mitosis and morphological changes of RIE-1 cells, such as inducing cell growth and invasion into surrounding stroma. In the absence of HGF, RIE-1 cells survived in the matrix but showed a lower growth rate. It is shown that blocking the MAP4K4 kinase-dependent signaling pathway specifically inhibits morphological changes caused by HGF.

The growth of adherent cells is determined by the downstream structure of the integrin receptor in the signal transduction pathway. Studies have examined the attachment and extension of RIE-1 cells expressing wild-type, activated and non-activated MAP4K4 on integrin gamete fibronectin, respectively. It was found that the kinase-active MAP4K4 inhibited cell expansion relative to non-vector-transfected clones, and the inactive MAP4K4 inhibited the growth of RIE-1 cells in soft agar, indicating that MAP4K4 plays a role in normal cell adhesion growth regulation. Cell invasion is the result of a combination of integrin receptor and cytoskeletal changes. Cell adhesion experiments showed that MAP4K4 negatively regulates the adhesion of RIE-1 cells to fibronectin.

Through scratch test and Boyden chamber invasion assay, MAP4K4 is highly expressed in ovarian cancer, breast cancer, melanoma and prostate cancer and is associated with cell invasion. Inhibition of MAP4K4 expression by SiRNA inhibits the invasive ability of cancer cells, and its signal pathway may be Rac1-MEKK1-MAP4K4-JNK-MAP1B, DCX, MAP2 and actin-related proteins (helix protein, paxillin).

Figure 1. Schematic diagram of suggested MAP4K4 downstream effectors and biological outcomes in cancer. (Gao, et al. 2016）

MAP4K4 Pathway in Tumors

MAP4K4 first activates a series of MAPKKKs, including MEKK1, MLL2, MLL3, YTPL2, DLK, TAO1, TAO2, TAK1, ASK1, ASK2, and then activates MEK4, which in turn phosphorylates the tyrosine residues of the TPY motif of JNK, resulting in JNK Transfer from the cytoplasm to the nucleus, which leads to a series of activation signals. MAP4K4 further phosphorylates the serine residue of p38 by activating TAK1, ASK2, DLK, MEKK4, TAO1/2/3, MLK2/3, MEK3, MEK4, MEK6, thereby transferring it from the cytoplasm to the nucleus, and series of activation signals occur. P38 phosphorylates Ser33 and Ser46 of p53 and increases the transcriptional activity of p53, leading to cell cycle arrest and apoptosis. In addition to MAPK/JNK, MAP4K4 has also been reported to play a role in the regulation of the MAPK / ERK1 / 2 pathway and the MAPK / p38 pathway in tumor cells.

References:

Gao, X. , Gao, C. , Liu, G. , & Hu, J. . (2016). Map4k4: an emerging therapeutic target in cancer. Cell and Bioscience,6(1).
Virbasius, J. V. , & Czech, M. P. . (2016). Map4k4 signaling nodes in metabolic and cardiovascular diseases. Trends in Endocrinology & Metabolism, S1043276016300224.
Feng, X. J. , Pan, Q. , Wang, S. M. , Pan, Y. C. , Wang, Q. , & Zhang, H. H. , et al. (2016). Map4k4 promotes epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma. Tumor Biology.

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