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Lobna's dissertation - OhioLink.pdf (3.57 MB)

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Regulation of the expression and activity of Extracellular signal-regulated kinase 3 (ERK3)

Elkhadragy, Lobna
http://orcid.org/0000-0001-8956-298X
http://rave.ohiolink.edu/etdc/view?acc_num=wright151359030649182

Abstract Details

2017, Doctor of Philosophy (PhD), Wright State University, Biomedical Sciences PhD.
Mitogen-activated protein kinases (MAPKs) are Ser/Thr kinases that regulate diverse cellular processes. Extracellular signal-regulated kinase 3 (ERK3) is an atypical MAPK that has recently gained interest for its roles in cancer. ERK3 promotes cancer cell migration, invasion and drug resistance, and its expression is upregulated in multiple cancers. However, little is known about the molecular mechanisms that regulate ERK3’s expression and kinase activity. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by inhibiting the expression of the tumor suppressor microRNA (miRNA) let-7i, which directly targets ERK3 mRNA. ERK3 then acts as an important downstream mediator of BMI1 in promoting cancer cell migration. Importantly, ERK3 protein level is positively correlated with BMI1 level in head and neck tumor specimens of human patients. In addition, we have investigated the roles of the activation loop phosphorylation and the unique elongated C-terminus extension in regulating ERK3’s kinase activity and functions in cancer cells. Our study revealed that mutating the activation loop phosphorylation site S189 or truncating the C-terminus extension greatly decreases ERK3’s in vitro kinase activity towards the oncogenic protein steroid receptor co-activator 3 (SRC-3), an important downstream target for ERK3 signaling in cancer. While the reduced activity of ERK3 S189A mutant can be partly attributed to its decreased interaction with the substrate SRC-3, the importance of the C-terminus extension in kinase activity possibly stems from its intramolecular interaction with the kinase domain of ERK3. In agreement with their decreased kinase activity towards SRC-3, the S189A mutant and the C-terminus deletion mutants have greatly diminished ability to stimulate migration and invasion of lung cancer cells as compared to wild type ERK3. Furthermore, we have identified a kinase-independent role of ERK3 in promoting cancer cell migration and invasion. Taken together, the findings of our study provide important insights into the molecular regulation of ERK3 signaling in cancer, which can accelerate the progress in developing anti-cancer therapeutic strategies through the inhibition of ERK3 signaling.
Weiwen Long, Ph.D. (Advisor)
Madhavi Kadakia, Ph.D. (Committee Member)
Steven Berberich, Ph.D. (Committee Chair)
Christopher Wyatt, Ph.D. (Committee Member)
Shulin Ju, Ph.D. (Committee Member)
156 p.
Biomedical Research; Molecular Biology
atypical MAPK; cancer; ERK3

Recommended Citations

Citations

  • Elkhadragy, L. (2017). Regulation of the expression and activity of Extracellular signal-regulated kinase 3 (ERK3) [Doctoral dissertation, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright151359030649182

    APA Style (7th edition)

  • Elkhadragy, Lobna. Regulation of the expression and activity of Extracellular signal-regulated kinase 3 (ERK3). 2017. Wright State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright151359030649182.

    MLA Style (8th edition)

  • Elkhadragy, Lobna. "Regulation of the expression and activity of Extracellular signal-regulated kinase 3 (ERK3)." Doctoral dissertation, Wright State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright151359030649182

    Chicago Manual of Style (17th edition)

wright151359030649182
274
© 2017, all rights reserved.
This open access ETD is published by Wright State University and OhioLINK.