Molecule Information

General Information of the Molecule (ID: Mol04381)

• Name: Mitogen-activated protein kinase 12 (MAPK12) ,Homo sapiens
• Synonyms: Extracellular signal-regulated kinase 6; Mitogen-activated protein kinase p38 gamma; Stress-activated protein kinase 3
• Molecule Type: Protein
• Gene Name: MAPK12
• Gene ID: 6300
• Sequence:
  MSSPPPARSGFYRQEVTKTAWEVRAVYRDLQPVGSGAYGAVCSAVDGRTGAKVAIKKLYR
  PFQSELFAKRAYRELRLLKHMRHENVIGLLDVFTPDETLDDFTDFYLVMPFMGTDLGKL
  M KHEKLGEDRIQFLVYQMLKGLRYIHAAGIIHRDLKPGNLAVNEDCELKILDFGLARQA
  DS EMTGYVVTRWYRAPEVILNWMRYTQTVDIWSVGCIMAEMITGKTLFKGSDHLDQLKE
  IMK VTGTPPAEFVQRLQSDEAKNYMKGLPELEKKDFASILTNASPLAVNLLEKMLVLDA
  EQRV TAGEALAHPYFESLHDTEDEPQVQKYDDSFDDVDRTLDEWKRVTYKEVLSFKPPR
  QLGAR VSKETPL
• Function: Serine/threonine kinase which acts as an essential componentof the MAP kinase signal transduction pathway. MAPK12 is one of thefour p38 MAPKs which play an important role in the cascades of cellularresponses evoked by extracellular stimuli such as pro-inflammatorycytokines or physical stress leading to direct activation oftranscription factors such as ELK1 and ATF2. Accordingly, p38 MAPKsphosphorylate a broad range of proteins and it has been estimated thatthey may have approximately 200 to 300 substrates each. Some of thetargets are downstream kinases such as MAPKAPK2, which are activatedthrough phosphorylation and further phosphorylate additional targets.Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cellssuggesting MAPK12 may inhibit cell proliferation while promotingdifferentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12in the cell nucleus increases its association with nuclear DLG1,thereby causing dissociation of DLG1-SFPQ complexes. This function isindependent of its catalytic activity and could affect mRNA processingand/or gene transcription to aid cell adaptation to osmolarity changesin the environment. Regulates UV-induced checkpoint signaling andrepair of UV-induced DNA damage and G2 arrest after gamma-radiationexposure. MAPK12 is involved in the regulation of SLC2A1 expression andbasal glucose uptake in L6 myotubes; and negatively regulates SLC2A4expression and contraction-mediated glucose uptake in adult skeletalmuscle. C-Jun phosphorylation is stimulated by MAPK14 andinhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 isrequired for the normal kinetochore localization of PLK1, preventschromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transientamplifying myogenic precursor cells during muscle growth andregeneration. {ECO:0000269|PubMed:10848581,ECO:0000269|PubMed:14592936, ECO:0000269|PubMed:17724032,ECO:0000269|PubMed:20605917, ECO:0000269|PubMed:21172807,ECO:0000269|PubMed:8633070, ECO:0000269|PubMed:9430721}.
• Uniprot ID: MK12_HUMAN
• Ensembl ID: ENSG0000018813014
• HGNC ID: HGNC:6874

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

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Dacomitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [1]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Dacomitinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: LDH assay; Flow cytometry assay
• Mechanism Description: Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity.

Clinical Trial Drug(s) 1 drug(s) in total

Vemurafenib/Cobimetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [2]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: Vemurafenib/Cobimetinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: Hs294T R cells; Skin; Homo sapiens (Human); CVCL_E3AI
• In Vitro Model: WM9 R cells; melanoma; Homo sapiens (Human); CVCL_E3AH
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time.

References

• Ref 1: Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells. Molecules. 2024 Jan 4;29(1):274.
• Ref 2: Characterization of two melanoma cell lines resistant to BRAF/MEK inhibitors (vemurafenib and cobimetinib). Cell Commun Signal. 2024 Aug 23;22(1):410.