MAP3K8
Description
The MAP3K8 (mitogen-activated protein kinase kinase kinase 8) is a protein-coding gene located on chromosome 10.
Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene. The gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/threonine-specific protein kinase family. This kinase can activate ERK1, ERK2 and p38 MAP kinases. This kinase was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This kinase was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. Studies of a similar gene in rat suggested the direct involvement of this kinase in the proteolysis of NF-kappaB1, p105 (NFKB1). This gene may also start transcription at a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity. In mice, the gene is known as TPL2 and is a tumor-suppressor gene whose absence contributes to the development and progression of cancer. However, it functions in other organs as a oncogene, promoting cancer.
MAP3K8 is essential for the activation of the MAPK/ERK pathway in macrophages in response to lipopolysaccharide (LPS) through TLR4, leading to the production of TNF-alpha (TNF), a pro-inflammatory cytokine crucial for immune responses. MAP3K8 is involved in regulating T-helper cell differentiation and IFNG expression in T-cells. It plays a role in host resistance to bacterial infection by negatively regulating type I interferon (IFN) production. In vitro, MAP3K8 activates the MAPK/ERK pathway independently of IRAK1 in response to IL1, resulting in increased IL8 and CCL4 expression. MAP3K8 transmits signals from CD40 and TNFRSF1A to activate ERK in B-cells and macrophages, potentially influencing immunoglobulin production. MAP3K8 might also be involved in TNF signaling that activates JNK and NF-kappa-B in certain cell types. In adipocytes, MAP3K8 activates the MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to lipolysis. MAP3K8 plays a role in the cell cycle. Isoform 1 exhibits some transforming activity, though it is less potent than the activated oncogenic variant.
MAP3K8 is also known as AURA2, COT, EST, ESTF, MEKK8, TPL2, Tpl-2, c-COT.
