Disease relevance of MAP3K8

• Mutational activation of the MAP3K8 protooncogene in lung cancer [1].
• We have identified MAP3K8 as a transforming gene from a human lung adenocarcinoma and characterized a 3' end mutation in the cDNA [1].
• We show that Tpl-2 is expressed in primary biopsies from patients with nasopharyngeal carcinoma and Hodgkin's disease, where LMP1 is also found [2].
• The Tpl-2 protein serine/threonine kinase was originally identified, in a C-terminally deleted form, as the product of an oncogene associated with the progression of Moloney murine leukemia virus-induced T cell lymphomas in rats [3].
• We have shown here that Tpl2/Cot is constitutively activated in human leukemia cell lines transformed by the human T cell leukemia virus type I (HTLV-I) [4].

Psychiatry related information on MAP3K8

• Improving Dietary Habits in Disadvantaged Women With HIV/AIDS: The SMART/EST Women's Project [5].
• In the SMART/EST II Women's Project 466 disadvantaged women with HIV/AIDS were randomized to one of four groups and received a two-phase training consisting of a coping skills/stress management and nutrition education provided either in a group or individually [5].

High impact information on MAP3K8

• These findings suggest the selective involvement of Cot/Tpl-2 or a closely related kinase in the CD3/CD28 costimulatory pathway leading to induced nuclear expression of NF-kappaB [6].
• The proto-oncogene Cot/Tpl-2 encodes a MAP3K-related serine-threonine kinase [6].
• Consistent with this hypothesis, immunoprecipitated Tpl-2 and Tpl-2deltaC (a C-terminally truncated mutant) phosphorylated and activated recombinant fusion proteins of the mammalian MAP kinase kinases, MEK-1 and SEK-1, in vitro [3].
• After Raf and Mos, Tpl-2 is the third serine/threonine oncoprotein kinase that has been shown to function as a direct activator of MEK-1 [3].
• The progesterone derivative 4,16-androstadien-3-one (AND) and the estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST) are candidate compounds for human pheromones [7].

Biological context of MAP3K8

• Depletion of ABIN-2 by RNA interference dramatically reduced steady-state levels of TPL-2 protein without affecting levels of TPL-2 mRNA or p105 protein [8].
• We demonstrate that knockdown of arrestin-2 leads to enhanced LPS-induced phosphorylation and degradation of p105, enhanced TPL2 release, and enhanced MEK1/2 phosphorylation [9].
• A 16-mer peptide sequence was obtained from the 12-kDa polypeptide which matched a new open reading frame from a human EST () encoding a hypothetical protein of unknown function [10].
• Inhibition of Tpl2 kinase and TNF-alpha production with 1,7-naphthyridine-3-carbonitriles: synthesis and structure-activity relationships [11].
• Approximately 70% of the ESTs generated in this study had not been captured during a previous EST project conducted using a cDNA library constructed from hand-dissected apex tissue that is highly enriched for SAMs [12].

Anatomical context of MAP3K8

• In addition, we confirmed that the mutation occurs in the original lung tumor, and we screened a series of lung cancer cell lines to determine whether the MAP3K8 mutation is a common occurrence in lung tumorigenesis [1].
• Consistently, in unstimulated bone marrow-derived macrophages (BMDMs), a substantial fraction of endogenous ABIN-2 was associated with both p105 and TPL-2 [8].
• RESULTS: Our results showed that Tpl2/Cot was overexpressed in all four patients with Large Granular Lymphocyte proliferative disorders (LGL-PDs) but in none of the remaining eight patients with other T-cell neoplasias [13].
• Furthermore, when smelling EST, they partly shared activation of the anterior hypothalamus with heterosexual men [7].
• In humans, the volatile C19-steroids androsta-4,16-dien-3-one (AND) and estra-1,3,5(10),16-tetraen-3-ol (EST) have been shown to modulate autonomic nervous system responses, and to cause hypothalamic activation in a gender-specific manner [14].

Associations of MAP3K8 with chemical compounds

• The Akt (or protein kinase B) and Cot (or Tpl-2) serine/threonine kinases are associated with cellular transformation [15].
• The tyrosine kinase Syk regulates TPL2 activation signals [16].
• The serine/threonine kinase Cot (also known as Tpl2) is a member of the MAP kinase kinase kinase (MAP3K) family that is known to regulate oncogenic and inflammatory pathways; however, the mechanism(s) of its regulation are not precisely known [17].
• EST dose-dependently inhibited 20K phosphorylation in platelets stimulated by thrombin, ionomycin or collagen [18].
• By employing a cell penetrating thiol protease inhibitor, EST: ethyl(+)-(2S,3S)-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)buty lcarbamoyl]- 2-oxiranecarboxylate, the role of calpain, a major thiol protease in platelets, on 20K protein (myosin light chain) phosphorylation was examined in intact human platelets [18].
• These inhibitors selectively target Tpl2 in these cells, and they block LPS- and IL-1beta-induced TNFalpha production in both primary human monocytes and human blood [19].
• Mutation of this conserved residue to alanine (A) blocked the ability of retrovirally expressed TPL-2 to induce the activation of ERK in LPS-stimulated Nfkb1(-/-) macrophages [20].

Regulatory relationships of MAP3K8

• Together, these data raise the possibility that ABIN-2 functions in the TLR4 signaling pathway which regulates TPL-2 activation [8].

Other interactions of MAP3K8

• Experiments using dominant-negative Tpl2 suggest this kinase functions distal to TRAFs but proximal to the TAK1/TAB1 signaling complex, within the IKK/NFkappaB activation pathway [21].
• Serum TNF-alpha levels were increased in all Tpl2/Cot overexpressing patients while serum IL-2 was undetectable in all subjects studied [13].
• Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling [17].
• The open reading frame of human EST encoded a polypeptide of 107 amino acids with a predicted molecular mass of 12.4 kDa, consistent with the experimental findings. p12 is 25% identical to S pombe Cdm1 [10].
• Upstream kinases involved in IKK complex activation such as TPL-2/COT, NIK, and IKKepsilon were also shown to play an important role in bpV-mediated NF-kappaB activation [22].

Analytical, diagnostic and therapeutic context of MAP3K8

• With powerful reverse genetics methods, a large collection of EST sequences and a new cDNA microarray, Gerbera has become a model plant of the sunflower family [23].
• Tpl-2 was found overexpressed in 14 of the 35 breast tumours tested using a semi-quantitative RT - PCR method [24].
• METHODS: In 46 patients with ApHCM, we measured CO time on M-mode echocardiography and corrected it by the R-R interval (cCOT) [25].
• EST/cDNA sequencing and microarray analysis show that nearly 70% are represented in embryo RNA [26].
• Although typical poly(A) sites are located between 0 and 2 kb from the stop codon, EST sequence analyses have identified sites located at unexpectedly long ranges (5-10 kb) in a number of genes [27].

References