{"id":{"repo_id":"ohiolink","oai_identifier":"oai:etd.ohiolink.edu:toledo1365165118"},"canonical_url":"https://search.dev.ndltd.org/etd/ohiolink/oai:etd.ohiolink.edu:toledo1365165118","repository":{"repo_id":"ohiolink","name":"OhioLINK","base_url":"https://etd.ohiolink.edu/acprod/odb_etd/ws/oai/oai"},"display":{"title":"The Regulatory Role of Mixed Lineage Kinase 4 Beta in MAPK Signaling and Ovarian Cancer Cell Invasion","abstract":"Mixed lineage kinase 4 (MLK4) is a member of the MLK family of mitogen-activated protein kinase kinase kinases (MAP3Ks). As components of a three-tiered signaling cascade, MAP3Ks promote activation of mitogen-activated protein kinase (MAPK), which in turn regulates different cellular processes including proliferation and invasion. Here, we show that the beta form of MLK4 (MLK4beta), unlike its close relative, MLK3, and other known MAP3Ks, negatively regulates the activities of the MAPKs, p38, ERK and JNK, even in response to stimuli such as sorbitol or TNFa. MLK4beta; also negatively regulates basal, but not TNFalpha-induced, NF-kappaB activity. Moreover, MLK4beta; undergoes autophosphorylation and has kinase activity towards histone H2A, but has no kinase activity towards the MAP2K, MEK4/SEK1, a known substrate for MLK3 and other MAP3Ks. Furthermore, MLK4beta interacts with MLK3 and inhibits MLK3 activation. In addition, MLK4 blocks matrix metalloproteinase-9 gelatinase activity and invasion in SKOV3 ovarian cancer cells, both of which are cellular responses that require MLK3. Collectively, our data establish MLK4beta as a novel suppressor of MLK3 activation, MAPK signaling and cell invasion.","abstract_html":"Mixed lineage kinase 4 (MLK4) is a member of the MLK family of mitogen-activated protein kinase kinase kinases (MAP3Ks). As components of a three-tiered signaling cascade, MAP3Ks promote activation of mitogen-activated protein kinase (MAPK), which in turn regulates different cellular processes including proliferation and invasion. Here, we show that the beta form of MLK4 (MLK4beta), unlike its close relative, MLK3, and other known MAP3Ks, negatively regulates the activities of the MAPKs, p38, ERK and JNK, even in response to stimuli such as sorbitol or TNFa. MLK4beta; also negatively regulates basal, but not TNFalpha-induced, NF-kappaB activity. Moreover, MLK4beta; undergoes autophosphorylation and has kinase activity towards histone H2A, but has no kinase activity towards the MAP2K, MEK4/SEK1, a known substrate for MLK3 and other MAP3Ks. Furthermore, MLK4beta interacts with MLK3 and inhibits MLK3 activation. In addition, MLK4 blocks matrix metalloproteinase-9 gelatinase activity and invasion in SKOV3 ovarian cancer cells, both of which are cellular responses that require MLK3. Collectively, our data establish MLK4beta as a novel suppressor of MLK3 activation, MAPK signaling and cell invasion.","abstract_has_math":false,"creators":["Abi Saab, Widian F."],"institution":"University of Toledo","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Biology (Cell-Molecular Biology)","degree_department":null,"school":null,"contributors":["Chadee, Dr. Deborah"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-07-11","date_published":"2013-07-11","updated_at":"2026-07-24T03:37:16Z","subjects":["Molecular Biology","MLK4beta","MLK3","MAPK signaling","Ovarian cancer cell invasion"],"languages":["English"],"rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. 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MLK4beta; also negatively regulates basal, but not TNFalpha-induced, NF-kappaB activity. Moreover, MLK4beta; undergoes autophosphorylation and has kinase activity towards histone H2A, but has no kinase activity towards the MAP2K, MEK4/SEK1, a known substrate for MLK3 and other MAP3Ks. Furthermore, MLK4beta interacts with MLK3 and inhibits MLK3 activation. In addition, MLK4 blocks matrix metalloproteinase-9 gelatinase activity and invasion in SKOV3 ovarian cancer cells, both of which are cellular responses that require MLK3. Collectively, our data establish MLK4beta as a novel suppressor of MLK3 activation, MAPK signaling and cell invasion."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","p.128","7.19 MB"]},{"key":"dc:title","label":"Title","values":["The Regulatory Role of Mixed Lineage Kinase 4 Beta in MAPK Signaling and Ovarian Cancer Cell Invasion"]}]}],"canonical_facts":{"dc:contributor":["Chadee, Dr. Deborah"],"dc:creator":["Abi Saab, Widian F."],"dc:date":["2013-07-11"],"dc:description":["Mixed lineage kinase 4 (MLK4) is a member of the MLK family of mitogen-activated protein kinase kinase kinases (MAP3Ks). As components of a three-tiered signaling cascade, MAP3Ks promote activation of mitogen-activated protein kinase (MAPK), which in turn regulates different cellular processes including proliferation and invasion. Here, we show that the beta form of MLK4 (MLK4beta), unlike its close relative, MLK3, and other known MAP3Ks, negatively regulates the activities of the MAPKs, p38, ERK and JNK, even in response to stimuli such as sorbitol or TNFa. MLK4beta; also negatively regulates basal, but not TNFalpha-induced, NF-kappaB activity. Moreover, MLK4beta; undergoes autophosphorylation and has kinase activity towards histone H2A, but has no kinase activity towards the MAP2K, MEK4/SEK1, a known substrate for MLK3 and other MAP3Ks. Furthermore, MLK4beta interacts with MLK3 and inhibits MLK3 activation. In addition, MLK4 blocks matrix metalloproteinase-9 gelatinase activity and invasion in SKOV3 ovarian cancer cells, both of which are cellular responses that require MLK3. Collectively, our data establish MLK4beta as a novel suppressor of MLK3 activation, MAPK signaling and cell invasion."],"dc:format":["application/pdf","p.128","7.19 MB"],"dc:identifier":["http://rave.ohiolink.edu/etdc/view?acc_num=toledo1365165118"],"dc:language":["English"],"dc:publisher":["University of Toledo / OhioLINK"],"dc:rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."],"dc:subject":["Molecular Biology","MLK4beta","MLK3","MAPK signaling","Ovarian cancer cell invasion"],"dc:title":["The Regulatory Role of Mixed Lineage Kinase 4 Beta in MAPK Signaling and Ovarian Cancer Cell Invasion"],"dc:type":["Electronic Thesis or Dissertation"],"thesis:degree_discipline":["Biology (Cell-Molecular Biology)"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["University of Toledo"]},"updated_at":"2026-07-24T03:37:16Z"}