Molecule Information

General Information of the Molecule (ID: Mol00486)

• Name: Mitogen-activated protein kinase kinase kinase 8 (MAP3K8) ,Homo sapiens
• Synonyms: Cancer Osaka thyroid oncogene; Proto-oncogene c-Cot; Serine/threonine-protein kinase cot; Tumor progression locus 2; TPL-2; COT; ESTF
• Molecule Type: Protein
• Gene Name: MAP3K8
• Gene ID: 1326
• Location: chr10:30434021-30461833[+]
• Sequence:
  MEYMSTGSDNKEEIDLLIKHLNVSDVIDIMENLYASEEPAVYEPSLMTMCQDSNQNDERS
  KSLLLSGQEVPWLSSVRYGTVEDLLAFANHISNTAKHFYGQRPQESGILLNMVITPQNGR
  YQIDSDVLLIPWKLTYRNIGSDFIPRGAFGKVYLAQDIKTKKRMACKLIPVDQFKPSDVE
  IQACFRHENIAELYGAVLWGETVHLFMEAGEGGSVLEKLESCGPMREFEIIWVTKHVLKG
  LDFLHSKKVIHHDIKPSNIVFMSTKAVLVDFGLSVQMTEDVYFPKDLRGTEIYMSPEVIL
  CRGHSTKADIYSLGATLIHMQTGTPPWVKRYPRSAYPSYLYIIHKQAPPLEDIADDCSPG
  MRELIEASLERNPNHRPRAADLLKHEALNPPREDQPRCQSLDSALLERKRLLSRKELELP
  ENIADSSCTGSTEESEMLKRQRSLYIDLGALAGYFNLVRGPPTLEYG
• 3D-structure: PDB ID: 4Y85; Classification: Transferase; Method: X-ray diffraction; Resolution: 2.33 Å
• Function: Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.
• Uniprot ID: M3K8_HUMAN
• Ensembl ID: ENSG00000107968
• HGNC ID: HGNC:6860

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [1]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8, colony formation, Transwell, and sphere-forming assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [2]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Rituximab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [2]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Sensitive Drug: Rituximab
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MAPK/BCR/PI signaling pathway; Regulation; N.A.
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Blue Cell Viability assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Esophageal cancer [ICD-11: 2B70]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Esophagus
• The Specified Disease: Esophageal cancer
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.70E-02; Fold-change: -7.83E-01; Z-score: -1.41E+00

References

• Ref 1: Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9. J Exp Clin Cancer Res. 2017 Dec 13;36(1):182. doi: 10.1186/s13046-017-0658-2.
• Ref 2: MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma. Blood Cancer J. 2017 Dec 15;7(12):654. doi: 10.1038/s41408-017-0033-8.