Menin determines K-RAS proliferative outputs in endocrine cells

Chester E. Chamberlain, David W. Scheel, Kathleen McGlynn, Hail Kim, Takeshi Miyatsuka, Juehu Wang, Vinh Nguyen, Shuhong Zhao, Anastasia Mavropoulos, Aswin G. Abraham, Eric O'Neill, Gregory M. Ku, Melanie H. Cobb, Gail R. Martin, Michael S. German

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Endocrine cell proliferation fluctuates dramatically in response to signals that communicate hormone demand. The genetic alterations that override these controls in endocrine tumors often are not associated with oncogenes common to other tumor types, suggesting that unique pathways govern endocrine proliferation. Within the pancreas, for example, activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas but are never found in pancreatic endocrine tumors. Therefore, we asked how cellular context impacts K-RAS signaling. We found that K-RAS paradoxically suppressed, rather than promoted, growth in pancreatic endocrine cells. Inhibition of proliferation by K-RAS depended on antiproliferative RAS effector RASSF1A and blockade of the RAS-activated proproliferative RAF/ MAPK pathway by tumor suppressor menin. Consistent with this model, a glucagon-like peptide 1 (GLP1) agonist, which stimulates ERK1/2 phosphorylation, did not affect endocrine cell proliferation by itself, but synergistically enhanced proliferation when combined with a menin inhibitor. In contrast, inhibition of MAPK signaling created a synthetic lethal interaction in the setting of menin loss. These insights suggest potential strategies both for regenerating pancreatic β cells for people with diabetes and for targeting menin-sensitive endocrine tumors.

Original languageEnglish (US)
Pages (from-to)4093-4101
Number of pages9
JournalJournal of Clinical Investigation
Volume124
Issue number9
DOIs
StatePublished - Sep 2 2014

ASJC Scopus subject areas

  • Medicine(all)

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    Chamberlain, C. E., Scheel, D. W., McGlynn, K., Kim, H., Miyatsuka, T., Wang, J., Nguyen, V., Zhao, S., Mavropoulos, A., Abraham, A. G., O'Neill, E., Ku, G. M., Cobb, M. H., Martin, G. R., & German, M. S. (2014). Menin determines K-RAS proliferative outputs in endocrine cells. Journal of Clinical Investigation, 124(9), 4093-4101. https://doi.org/10.1172/JCI69004