The Regulatory Role of Mixed Lineage Kinase 4 Beta in MAPK Signaling and Ovarian Cancer Cell Invasion

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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biology (Cell-Molecular Biology)

Grantor dc:publisher

University of Toledo

Year dc:date

2013

Author dc:creator

• Abi Saab, Widian F.

Contributors dc:contributor

• Chadee, Dr. Deborah

• Molecular Biology
• MLK4beta
• MLK3
• MAPK signaling
• Ovarian cancer cell invasion

Statement 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.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=toledo1365165118

OAI identifier oai:identifier

oai:etd.ohiolink.edu:toledo1365165118