Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) – also known as hepatocyte progenitor kinase-like/germinal center kinase-like kinase (HGK) and Nck-interacting kinase (NIK) – is an enzyme, specifically a serine/threonine (S/T) kinase encoded by the MAP4K4 gene in humans.
MAP4K4 is involved in a wide array of physiological processes including cell migration, proliferation and adhesion; its activity has been implicated in systemic inflammation, metabolic disorders, cardiovascular disease and cancer.
While MAP4K4 has been found to be upregulated in a wide array of cancers, there is currently limited information regarding its specific involvement. However, there is increasing evidence that suggests MAP4K4 has an important role in the development and progression of cancer, and may serve as a novel target for cancer therapeutics.
Discovery and classification
MAP4K4 is categorized under the mammalian sterile 20 protein (Ste20p) kinase family due to its shared homology with the Ste20p kinase found in budding yeast and is a member of the GCK-IV subfamily. Mammalian MAP4K4 was initially identified in mice as a kinase activator for a protein called Nck followed shortly by identification and cloning of the human orthologue encoded by the MAP4K4 gene.
Structure and expression
In humans, MAP4K4 is encoded by the MAP4K4 gene located on chromosome 2, position q11.2 and consists of 33 exons responsible for its synthesis. It contains approximately 1200 amino acids, has a molecular mass of ~140 KDa. and its orthologues across various species share molecular and structural similarities.
Structurally MAP4K4 contains the following domains: N-Terminal Kinase Domain Coiled-coil domain C-Terminal Hydrophobic Leucine-Rich Citron Homology Domain (CNH) Interdomain - Connects the kinase and CNH domains, facilitates protein-protein interactions. Although it has been identified, its structural components and functionality are currently poorly understood
Alternative splicing of the MAP4K4 gene yields five functional isoforms, all of which display fully homologous kinase and CNH domains but differences in the interdomain domain. While the biological significance of these isoforms remains to be determined, it can be speculated that such variations alter and determine MAP4K4's interactions with other proteins and factors, ultimately leading to the activation/inhibition of different biochemical and physiological cascades.
The mammalian class of Ste20 kinases require phosphorylation at specific sites for full activity. Primary phosphorylation at the activation site in their kinase domain is believed to cause a conformational change in the protein, stabilizing the structure of its activation segment to allow suitable substrate binding. Secondary sites also require phosphorylation for the enzyme to assume full activation and is achieved via autophosphorylation or by upstream kinases.
To date, MAP4K4 has been found to be expressed in all tissue types with a relatively more pronounced expression in the brain and testes. Multiple isoforms of MAP4K4 can be present at any given time in the same cell but the abundance of each isoform in the cell differs depending on the cell-type or tissue-type. E.g. In humans, the shorter isoform of MAP4K4 is predominantly expressed in organs including the liver, placenta, skeletal muscles while a longer isoform is expressed in the brain
Interactions and signaling
TNF-α
Evidence from mammalian and fly studies indicate that MAP4K4 is involved with tumour necrosis factor alpha (TNF-α) and its c-jun N-terminal kinase (JNK) signaling pathway. MAP4K4 not only mediates TNF-α signaling but also promotes its expression; moreover, TNF-α can elevate MAP4K4 expression using transcription factors
The JNK pathway is implicated in a number of physiological processes and involves JNKs – kinases responsible for the phosphorylation of a downstream protein called c-Jun. This further leads to the increase in expression and activity of specific transcription factors that respond to a variety of cellular stressors, growth factors and cytokines. The activation of the JNK signal transduction pathway by MAP4K4 has been implicated in apoptotic regulation of many different cell types, tumorigenesis and/or inflammation.
p53
p53 is a tumour suppressor gene and is involved with cellular response to stress. When expressed, the cell cycle is halted in the G1 phase and can induce senescence or apoptosis. Mutations to the p53 gene are often found in many types of cancers.