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Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.
Gene References into Functions
These results suggest that in the early response to stressful stimuli, MLK4beta-MLK3 binding is important for regulating MLK3 activity and MAPK signalling, and after prolonged periods of stress exposure, MLK4beta and MLK3 proteins decline via CHIP-dependent degradation. PMID: 28757353
In summary, this investigation identifies an EGFR-DOCK180-RAC1-MLK3-JNK signaling axis that drives glioblastoma cell migration and dissemination.IMPLICATIONS: On the basis of these findings, MLK3 emerges as a potential therapeutic target for the treatment of glioblastoma PMID: 28487380
chronic hypoxia can reduce MLK3 expression in a posttranscriptional regulatory manner. PMID: 28555332
Data indicate that BTG2, MAP3K11, RPS6KA1 and PRDM1 as putative targets of microRNA miR-125b. PMID: 27613090
Increased expression of MAP3K11 is associated with esophageal cancer. PMID: 26717044
MLK3 serves as a common upstream kinase of AMPK and JNK and functions as a direct upstream kinase for AMPK independent of LKB1 PMID: 25874865
MLK3 represents a newly recognized integral component of HER2 biology in HER2+ breast tumors. PMID: 26152725
MLK3 is a critical factor controlling the activity of kinase networks that control the cellular responses to different concentrations of reactive oxygen species. PMID: 24894995
Signaling pathways associated with the Pro252His mutation in MLK3 are located in the kinase domain which is an important domain for the regulation of downstream signaling pathways. PMID: 24628919
CHIP modulates MLK3 protein levels in response to Geldanamycin and stress stimuli, and CHIP-dependent regulation of MLK3 is required for suppression of SKOV3 ovarian cancer cell invasion. PMID: 24912674
Data indicate URMC-099 as an orally bioavailable, potent mixed lineage kinase 3 MLK3 inhibitor. PMID: 24044867
NS5A targets MLK3 with multiple downstream consequences for both apoptosis and K(+) homeostasis. PMID: 23857585
Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic beta cell death PMID: 23172226
High MAP3K11 expression is associated with prostate cancer. PMID: 22761715
Findings suggest that the MLK3-JNK-paxillin signaling axis may represent a potential prognostic marker in breast cancer metastasis. PMID: 22700880
Data suggest that MEKK2 and MLK3 represent untargeted kinases in tumor biology for potential therapeutic development. PMID: 22139075
The findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells. PMID: 22652451
These findings collectively suggest that the MLK3-Pin1 signaling cascade plays a critical role in regulating the cell cycle, centrosome numbers, and oncogenesis. PMID: 22566623
Data show that HBx can induce HepG2 cell apoptosis via a novel active MLK3-MKK7-JNKs signaling module to upregulate FasL protein expression. PMID: 22509080
co-expression of MLK3 and beta-catenin resulted in significant G(2)/M arrest. PMID: 21880738
These results establish merlin as a potent inhibitor of mixed lineage kinase 3, extracellular signal-regulated kinase, and c-jun N-terminal kinase activation in cancer. PMID: 20890305
MLK3 is critical for breast cancer cell migration and promotes cell transformation. PMID: 20514022
Studies indicate that the MLK3/JNK1 axis mediates G17-induced gastric cancer cell migration, which can be targeted for designing novel therapeutic strategies for treating gastric malignancies. PMID: 20150185
Novel proteolytic processing of MLK3 may negatively control MLK3 signalling to JNK. PMID: 20158498
MLK3 mutations is associated with the mismatch repair deficiency in gastrointestinal cancer. PMID: 19955118
Estradiol inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug-induced death of ER(+) breast cancer cells. PMID: 20145118
MLK3 functions to limit IKK activity, and depleting MLK3 helps protect cells from etoposide-induced cell death through activation of IKK-dependent signaling. PMID: 19782705
MLK3 may be a negative regulator of the growth-promoting and transforming properties of Rac1 PMID: 11713255
Twelve in vivo MLK3 phosphorylation sites have been identified. PMID: 11969422
negative regulation by protein kinase B leads to cell survival PMID: 12458207
MLK3 is phosphorylated by Akt2, which results in the disassembly of the JNK complex bound to POSH and down-regulation of the JNK signaling pathway PMID: 14504284
These observations support a role for mixed lineage kinases, including MLK3, in the TGF-beta1-induced cell death mechanism. PMID: 15069087
MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. PMID: 15258589
The MLK3 might be a unique target to selectively inhibit transformed cell proliferation by disrupting mitotic spindle formation resulting in mitotic arrest. PMID: 15923109
Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3 PMID: 16253996
Merlin and MLK3 can interact in situ and merlin can disrupt the interactions between B-Raf and Raf-1 or those between MLK3 and either B-Raf or Raf-1. PMID: 16537381
JNK-mediated feedback phosphorylation of MLK3 regulates its activation and deactivation states by cycling between Triton-soluble and Triton-insoluble forms PMID: 16687404
a direct link between GSK-3beta and MLK3 activation in a neuronal cell death pathway and identify MLK3 as a direct downstream target of GSK-3beta. PMID: 17711861
p38 MAPK inhibitors SB202190 and SB203580 activated JNK via MLK-3/MKK7 pathway. PMID: 18222647
findings demonstrate a scaffolding role for MLK3 in controlling the extent of Rho activation that modulates cell migration PMID: 18851832
K48-linked ubiquitination directs Mixed lineage kinase 3 for proteosomal degradation while K63-linked ubiquitination is important for Mixed lineage kinase 3 kinase activity. PMID: 19586614
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Subcellular Location
Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Note=Location is cell cycle dependent.
Protein Families
Protein kinase superfamily, STE Ser/Thr protein kinase family, MAP kinase kinase kinase subfamily
Tissue Specificity
Expressed in a wide variety of normal and neoplastic tissues including fetal lung, liver, heart and kidney, and adult lung, liver, heart, kidney, placenta, skeletal muscle, pancreas and brain.