The goal of this project is to determine the mechanistic differences in MEK/ERK signaling that mediates growth arrest versus cell proliferation in response to aberrant Ras and/or Raf signals. Aberrant activation of the Ras/Raf/MEK/ERK pathway is a central feature in many cancers. However, paradoxically, sustained activation of the pathway induces cell cycle arrest and senescence in normal cells and certain cancer types. It has been proposed that growth arrest acts as a defense mechanism against Ras/Raf-mediated carcinogenesis and that overcoming this "growth arrest barrier" is a necessary step in tumor progression. Our understanding of this key event in carcinogenesis, controlled at the level of MEK/ERK, is currently quite limited. We have begun to address the underlying mechanisms of MEK/ERK signaling using normal and Ras/Raf-responsive tumor cells as models. The first intriguing finding is that ERK can mediate growth arrest by utilizing not only its "canonical" kinase activity but also, as yet unidentified, non-catalytic functions. We recently reported that oncogenic Raf signal-induced growth arrest is abrogated by ERK1/2 depletion but introduction of catalytically disabled mutant ERK into ERK1/2- depleted cells can selectively restore the growth arrest phenomenon. Based upon a hypothesis that MEK/ERK would interact with specific proteins to mediate growth arrest signaling, we conducted tandem affinity purification and identified mortalin as a potential negative regulator of MEK/ERK-growth arrest signaling. Our preliminary studies show that mortalin binds to inactive, but not active, MEK and that mortalin depletion increases basal as well as Raf-induced MEK/ERK activity. In addition, mortalin depletion promotes growth inhibitory signaling whereas mortalin overexpression exerts the opposite effects. These preliminary studies suggest that MEK/ERK utilizes a unique signaling mechanism to mediate growth arrest, for which mortalin has a negative-regulatory role possibly via its physical interaction with the pathway and ERK modulates a mechanism that requires its non-catalytic function. To test these hypotheses, we propose to (i) determine the role of mortalin in the regulation of Raf/MEK/ERK-mediated growth arrest signaling by gain or loss of function studies in normal and K-Rasor B-Raf mutated tumor cells and by comparing mortalin expression levels with altered MEK/ERK activity in tumor tissue specimens;(ii) determine whether mortalin regulates the Raf/MEK/ERK pathway by differentially sequestering MEK1 or MEK2;and (iii) determine molecular mechanisms underlying the non-catalytic ERK functions. This study will enhance our knowledge of the specific mechanisms of MEK/ERK signaling that interrupts Ras/Raf-driven carcinogenesis.

Public Health Relevance

Activation of the MEK/ERK pathway induces terminal growth arrest in certain types of cancer lines derived from small cell lung carcinoma, medullary thyroid carcinoma, prostate carcinoma, pheochromocytoma, glioma, and gastrointestinal carcinoid. Exploration of the possibility that these cancer types can be effectively suppressed by modulating the pathway via mortalin into the direction of growth arrest may allow development of new therapeutic strategies to control them.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Watson, Joanna M
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Medical College of Wisconsin
Schools of Medicine
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Starenki, D; Hong, S-K; Lloyd, R V et al. (2015) Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. Oncogene 34:4624-34
Sosonkina, Nadiya; Hong, Seung-Keun; Starenki, Dmytro et al. (2014) Kinome sequencing reveals RET G691S polymorphism in human neuroendocrine lung cancer cell lines. Genes Genomics 36:829-841
Park, Jong-In (2014) Growth arrest signaling of the Raf/MEK/ERK pathway in cancer. Front Biol (Beijing) 9:95-103
Kim, Jin-Hwan; Hong, Seung-Keun; Wu, Pui-Kei et al. (2014) Raf/MEK/ERK can regulate cellular levels of LC3B and SQSTM1/p62 at expression levels. Exp Cell Res 327:340-52
Sosonkina, Nadiya; Starenki, Dmytro; Park, Jong-In (2014) The Role of STAT3 in Thyroid Cancer. Cancers (Basel) 6:526-44
Hong, Seung-Keun; Kim, Jin-Hwan; Starenki, Dmytro et al. (2013) Autophagy sensitivity of neuroendocrine lung tumor cells. Int J Oncol 43:2031-8
Wu, Pui-Kei; Hong, Seung-Keun; Veeranki, Sudhakar et al. (2013) A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase. Mol Cell Biol 33:4051-67
Starenki, Dmytro; Singh, Nishant K; Jensen, Davin R et al. (2013) Recombinant leukemia inhibitory factor suppresses human medullary thyroid carcinoma cell line xenografts in mice. Cancer Lett 339:144-51
Hong, Seung-Keun; Jeong, Joseph H; Chan, Andrew M et al. (2013) AKT upregulates B-Raf Ser445 phosphorylation and ERK1/2 activation in prostate cancer cells in response to androgen depletion. Exp Cell Res 319:1732-43
Starenki, Dmytro; Park, Jong-In (2013) Mitochondria-targeted nitroxide, Mito-CP, suppresses medullary thyroid carcinoma cell survival in vitro and in vivo. J Clin Endocrinol Metab 98:1529-40

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