Disease relevance of MAP3K10

• We have isolated a cDNA fragment of the MST gene from the MKN28 gastric cancer cell line cDNA pool by degenerate polymerase chain reaction [1].
• MLK2 RNA was also absent from the testis of rats after induced cryptorchidism [2].
• Furthermore, over-expression of the N terminus of normal huntingtin partially rescues the neuronal toxicity induced by MLK2 [3].
• The recovery of circulating antigen-specific T-cell immunity to Epstein-Barr virus (EBV) was determined in ELIspot assays following allogeneic myeloablative or nonmyeloablative stem cell transplantation (MST/NST) [4].
• ESI/MST/MS of model compounds found characteristic water loss from alcohol dehydration and anhydride formation, as well as CO2 loss from decarboxylation, and CO loss from ester structures [5].

Psychiatry related information on MAP3K10

• Furthermore, dominant-negative MLK2 blocked apoptosis induced by polyglutamine-expanded huntingtin protein, the product of the mutant Huntington's disease gene [6].
• Novel treatments of mood disorders based on brain circuitry (ECT, MST, TMS, VNS, DBS) [7].

High impact information on MAP3K10

• Many cortical neurons in visual areas V1 (ref. 2), MT (refs 3, 4) and MST (refs 5, 6) that are tuned to binocular disparity are also tuned to orientation, motion direction and speed [8].
• In an attempt to identify proteins that affect the activity and localization of MLK2, we have screened a yeast two-hybrid cDNA library [9].
• When expressed in fibroblasts, MLK2 co-localizes with active, dually phosphorylated JNK1/2 to punctate structures along microtubules [9].
• Such disparity detectors were found in cortical visual areas V1, V2, V3, V3A, VP, MT (V5) and MST of monkeys and in the superior colliculus of the cat and opossum [10].
• In addition, we demonstrated that endogenous MLK2 co-immunoprecipitates with clathrin heavy chain from the vesicle-enriched fraction of mouse brain lysate [11].

Chemical compound and disease context of MAP3K10

• We compared the effects of amlodipine and verapamil slow release on autonomic responses to a 5-min mental arithmetic test (MST) in patients with mild to moderate hypertension [12].
• In this paper we evaluate the cytokine expression patterns of T-cells and the plasmatic levels of nitrite and nitrate in patients with localized cutaneous leishmaniasis (LCL) as well as endemic non-infected individuals with positive (MST) and negative (NI) Montenegro skin test, without previous history of leishmanial lesions [13].

Biological context of MAP3K10

• In addition, the deletion analysis on MST/MLK2 showed that the kinase domain is responsible for the determination of substrate specificity [14].
• Cloning and characterization of MST, a novel (putative) serine/threonine kinase with SH3 domain [1].
• The MST gene was moderately expressed in brain, skeletal muscle and testis as a 3.8 kb mRNA, and the MST gene has been mapped to human chromosome 19q13.1-q13.2 [1].
• The deduced amino acid sequence corresponding to a part of kinase domain and leucine zipper domains of MST (amino acid codons 244-461) is almost identical to the published partial amino acid sequence of MLK2 [1].
• The predicted MLK2 polypeptide has 954 amino acids and contains a src homology 3 (SH3) domain, a kinase catalytic domain, a double leucine zipper and basic domain, and a large C-terminal domain [15].

Anatomical context of MAP3K10

• When used as a probe to examine mRNA expression in human tissues, a MLK2 cDNA hybridised to a species of 3.8 kb that was expressed at highest levels in RNA from brain and skeletal muscle [15].
• In RNA from isolated cell types, a MLK2 transcript was detected in primary spermatocytes and round spermatids, but not in Leydig or Sertoli cells [2].
• These findings indicate the JNK pathway is most likely ubiquitous in rodent testicular cells, while the cell-specific pattern of MLK2 expression suggests that it may be involved in the regulation of processes specific to post-mitotic germ cells [2].
• Furthermore, the finding of MLK2 protein in the nucleus of spermatocytes and round spermatids indicates a role for MLK2 in regulation of nuclear events specific to germ cell development [2].
• Mixed lineage kinase 2 interacts with clathrin and influences clathrin-coated vesicle trafficking [11].

Associations of MAP3K10 with chemical compounds

• Nucleotide sequence analysis indicated that the MST gene encodes a novel putative non-receptor type of serine/threonine kinase with Src homology 3 (SH3) domain, two leucine zipper domains and proline rich domain [1].
• We find that normal huntingtin interacts with MLK2, whereas the polyglutamine expansion interferes with this interaction [3].
• Recently we showed that MLK2 causes apoptosis in cultured neuronal cells and that this effect is dependent on activation of the JNK pathway (Liu, Y. F., Dorow, D. S., and Marshall, J. (2000) J. Biol. Chem. 275, 19035-19040) [6].
• Cotransfection of dominant-negative JNK kinase inhibits phosphorylation of kinase-negative MLK2 by anisomycin-activated JNK [6].
• The mixed lineage kinase 2 (MLK2) protein contains several structurally distinct domains including an src homology (SH) 3 domain, a kinase catalytic domain, two leucine zippers, a basic motif and a cdc42/rac interactive binding motif [16].

Physical interactions of MAP3K10

• Here, we isolated the mixed lineage kinase 2 (MLK2) as an interacting partner for the corepressor Alien using a yeast two hybrid screen [17].

Enzymatic interactions of MAP3K10

• Activated JNK phosphorylates the c-terminal domain of MLK2 that is required for MLK2-induced apoptosis [6].
• Phosphopeptide mapping of MLK2 proteins revealed that activated JNK2 phosphorylates multiple sites mainly within the noncatalytic C-terminal region of MLK2 including the C-terminal 100 amino acid peptide [6].

Regulatory relationships of MAP3K10

• Furthermore, we show that the N-terminal region of MLK2 is sufficient to activate JNK but that removal of the C-terminal domain abrogates the apoptotic response [6].

Other interactions of MAP3K10

• We have examined expression of both MLK2 and SEK1/JNKK RNAs in the rat testis at various times during postnatal development and in isolated testicular cell populations [2].
• Adenoviral dominant negative constructs of two other MLK family members (MLK 2 and DLK) did not protect against MPP(+)-induced cell death [18].
• The critical proline residue in the SH3-binding site of MLK3 is conserved in the closely related family members, MLK1 and MLK2, suggesting a common autoinhibitory mechanism among these kinases [19].
• We demonstrate that clathrin binding requires a motif (LLDMD) located near the MLK2 C terminus, which is similar to "clathrin box" motifs important for binding of clathrin coat assembly and accessory proteins to the clathrin heavy chain [11].

Analytical, diagnostic and therapeutic context of MAP3K10

• We also have used immunohistochemistry to examine MLK2 protein expression and localization in adult rat and mouse testis [2].
• We used immunoprecipitation and mass spectrometric analysis to identify MLK2-binding proteins in cell lines with inducible expression of green fluorescent protein-tagged MLK2 [11].
• The activity in the human MT/MST homolog measured by functional magnetic resonance imaging (fMRI) was significantly higher in both the translation and the expansion conditions than in the passive condition, while the activity in area V1 was significantly higher only in the translation condition [20].
• RESULTS: Treatment with Chi220 for 14 days prolonged renal allograft survival (MST 38.5 vs. 7 days in untreated controls) [21].
• We have studied the kinetic profile of controlled release morphine (MST) in 12 patients with posthepatitic cirrhosis, caused by HCV and HBsAg, with portal hypertension, given MST 30 mg for endoscopic sclerotherapy and compared the data with those from 10 healthy controls [22].

References