title: 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.forename: Chester E
authors.initials: CE
authors.lastname: Chamberlain
authors.forename: David W
authors.initials: DW
authors.lastname: Scheel
authors.forename: Kathleen
authors.initials: K
authors.lastname: McGlynn
authors.forename: Hail
authors.initials: H
authors.lastname: Kim
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyatsuka
authors.forename: Juehu
authors.initials: J
authors.lastname: Wang
authors.forename: Vinh
authors.initials: V
authors.lastname: Nguyen
authors.forename: Shuhong
authors.initials: S
authors.lastname: Zhao
authors.forename: Anastasia
authors.initials: A
authors.lastname: Mavropoulos
authors.forename: Aswin G
authors.initials: AG
authors.lastname: Abraham
authors.forename: Eric
authors.initials: E
authors.lastname: O'Neill
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Ku
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
authors.forename: Gail R
authors.initials: GR
authors.lastname: Martin
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
chemical_list: C117307:KRAS protein, human; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins