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
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
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Research Article

Menin determines K-RAS proliferative outputs in endocrine cells

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.

Authors

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

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Figure 1

Pancreatic endocrine mass in Kras-het mice.

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Pancreatic endocrine mass in Kras-het mice. (A and B) Schematic in A ill...
(A and B) Schematic in A illustrates the relationship between K-RAS-GTP binding and intracellular signaling; schematic in B illustrates the conversion of the transcriptionally silent KrasG12D–knock-in allele, which contains the G12D mutation in exon 2 and an upstream LoxP-Stop-LoxP sequence (12), to an active allele expressing constitutively active K-RASG12D after Cre-mediated recombination. (C and D) Projection images of the dorsal pancreas were collected by whole-mount confocal microscopy from E13.5 mouse embryos of the indicated genotypes and immunostained for E-cadherin (blue) and glucagon and insulin (green) (n = 6 Kras WT, n = 6 Kras-het). (E) Quantification of immunostained areas in the epithelial pancreas (E-cadherin) and endocrine pancreas (glucagon and insulin) relative to WT embryos. (F–H) Pancreatic sections from P5 WT (F) and Kras-het (G) neonates were immunostained for glucagon (red) and insulin (green), with quantification of the relative insulin and glucagon areas and pancreatic mass (H) (n = 3 Kras WT, n = 3 Kras-het). All data points represent the mean ± SEM. **P < 0.01 versus WT animals by 2-tailed Student’s t test. Scale bars: 50 μm.