Disease relevance of MAP3K1

• MEKK1 induced AR-dependent apoptosis in prostate cancer cells [1].
• Lysophosphatidic Acid Stimulates Ovarian Cancer Cell Migration via a Ras-MEK Kinase 1 Pathway [2].
• Instead, LPA induces the redistribution of focal adhesion kinase to focal contact regions of the cytoplasm membrane, and this event is abolished by pertussis toxin, dominant negative H-Ras, or dominant negative MEKK1 [2].
• Dominant negative MEKK1 inhibits survival of pancreatic cancer cells [3].
• HTLV-I Tax protein binds to MEKK1 to stimulate IkappaB kinase activity and NF-kappaB activation [4].

High impact information on MAP3K1

• In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity [5].
• Furthermore, recombinant MEKK1 stimulates IKKbeta phosphorylation of IkappaB alpha [4].
• MEKK1 indirectly suppresses NF-AT4 nuclear import by stabilizing the interaction between NF-AT4 and CKIalpha [6].
• Eukaryotic cells respond to different extracellular stimuli by recruiting homologous signalling pathways that use members of the MEKK, MEK and ERK families of protein kinases [7].
• Latest results indicate that caspase-mediated cleavage of the first component of this latter pathway, MEKK-1, may trigger activation of this pathway in anoikis [8].

Chemical compound and disease context of MAP3K1

• MEKK1 activation of human estrogen receptor alpha and stimulation of the agonistic activity of 4-hydroxytamoxifen in endometrial and ovarian cancer cells [9].
• Cisplatin-resistance involves the defective processing of MEKK1 in human ovarian adenocarcinoma 2008/C13 cells [10].

Biological context of MAP3K1

• These results strongly suggest that Ser222 represents one key MAPKKK-dependent phosphorylation site switching on and off the activity of MAPKK, an event crucial for growth control [11].
• Mutation of that response element abrogated MEKK1-mediated FasL promoter activation and interfered in stress-induced activation of that promoter [12].
• Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function [1].
• Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase [13].
• MEKK1 has a plant homeobox domain (PHD) that has been shown to have E3 ligase activity [14].

Anatomical context of MAP3K1

• Stress-induced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter [12].
• Taken together, our data indicate that MEKK1 and transcription factors regulated by the JNK pathway play a role in committing lymphocytes to undergo apoptosis by inducing FasL expression via a novel response element in the promoter of that gene [12].
• MEKK1 is a MAPK kinase kinase that is activated in response to stimuli that alter the cytoskeleton and cell shape [14].
• To study the significance of the JNK cascade in T lymphocytes, we established stable Jurkat cell lines that inducibly express dominant active (DA) or dominant negative (DN) MEKK-1 [15].
• These data indicate that in neutrophils activation of MEKK in addition to Raf may underlie stimulation of MAP kinase and other MAP kinase homologues by FMLP [16].

Associations of MAP3K1 with chemical compounds

• Activation of the AR by dihydrotestosterone (DHT) regulates diverse physiological functions including secondary sexual differentiation in the male and the induction of apoptosis by the JNK kinase, MEKK1 [1].
• Kinase-inactive MEKK1 inhibits Stat3 phosphorylation on tyrosine and serine, and its transcriptional activity stimulated by epidermal growth factor and platelet-derived growth factor in different cell types [17].
• The interaction is prevented by mutation of the essential cysteine in the MEKK1 PHD domain [18].
• These data demonstrate for the first time a novel role of MEKK1 to modulate tyrosine kinases that results in the activation of specific members of STAT family [17].
• Taken together, these data demonstrate that MLK7 is the MAPKKK required for modulation of the stress-activated MAPKs downstream of anisomycin and UV stimulation and that DHP-2 can be used to block MLK7 pathway activation in cells as well as in vivo [19].

Physical interactions of MAP3K1

• We showed previously that MEKK1 binds directly to JNK/SAPK [20].
• MEKK1 binds raf-1 and the ERK2 cascade components [20].
• RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity [18].

Enzymatic interactions of MAP3K1

• MEK is phosphorylated and activated by either Raf or MEK kinase (MEKK) [21].
• The results also demonstrated that PKCbeta phosphorylated and activated MEKK-1 in vitro [22].

Regulatory relationships of MAP3K1

• However, only S222A/MAPKK showed a reduction in phosphorylation in response to active MAPKKK and exerted a dominant negative effect on the serum-stimulated endogenous MAPKK [11].
• This compound also prevents activation of both IKKs and DNA binding of NF-kappa B induced by MEKK and NF-kappa B-inducing kinase [23].
• MEK kinase 1 is essential for Bcr-Abl-induced STAT3 and self-renewal activity in embryonic stem cells [24].
• TNF-alpha treatment induced both Ras and MEKK1 activation [25].
• Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kappaB-mediated gene expression in airway epithelial cells [25].

Other interactions of MAP3K1

• MLK3 cooperated with the other two IKKKs, MEKK1 and NF-kappaB-inducing kinase, in the induction of IKK activity [26].
• In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to phosphorylate stress-activated protein kinase [27].
• Parthenolide targets a component of the I kappa B kinase complex without directly inhibiting IKK alpha, IKK beta, or MEKK1 [23].
• Activation of MEKK by formyl-methionyl-leucyl-phenylalanine in human neutrophils. Mapping pathways for mitogen-activated protein kinase activation [16].
• Western blot analysis of FLS demonstrated that MEKK1, MEKK2, and TAK1 were readily detectable and were subsequently the focus of functional studies [28].

Analytical, diagnostic and therapeutic context of MAP3K1

• The difference of suppression in pancreatic cancer cells and non-pancreatic cancer cells suggested that the MEKK1 pathway mainly contributes to cell survival in pancreatic cancer cells and may provide an advantage for the gene therapy of pancreatic cancers using DN-MEKK expression vectors [3].
• Western data showed that NOx increased the expressions of c-Fos, c-Jun, and signaling kinases including MEKK1, JNK1, and p38 (with induction fold of 3.3, 2.8, and 3.2, respectively) in the cells 12 h after treatment [29].
• Confocal immunofluorescence microscopy of COS cells demonstrated differential MEKK subcellular localization: MEKK1 was nuclear and in post-Golgi vesicular-like structures; MEKK2 and 4 were localized to distinct Golgi-associated vesicles that were dispersed by brefeldin A [30].
• Gel-shift/super gel-shift analyses identified c/EBPbeta dimers and c/EBPbeta/NF-kappaB p65 heterodimers as binding species at the apparent site of MEKK1-dependent transactivation [31].
• Immunoblotting experiments revealed about 10-fold more c-Raf in the membranes from E1A/ras cells than from E1A/E1B cells, and 50-60% of the MAPKKK activity in Triton X100-solubilised membranes from E1A/ras cells was immunoprecipitated with anti-Raf antibodies [32].

References