Details

Autor(en) / Beteiligte

• Nissim, Sahar
• Leshchiner, Ignaty
• Mancias, Joseph D.
• Greenblatt, Matthew B.
• Maertens, Ophélia
• Cassa, Christopher A.
• Rosenfeld, Jill A.
• Cox, Andrew G.
• Hedgepeth, John
• Wucherpfennig, Julia I.
• Kim, Andrew J.
• Henderson, Jake E.
• Gonyo, Patrick
• Brandt, Anthony
• Lorimer, Ellen
• Unger, Bethany
• Prokop, Jeremy W.
• Heidel, Jerry R.
• Wang, Xiao-Xu
• Ukaegbu, Chinedu I.
• Jennings, Benjamin C.
• Paulo, Joao A.
• Gableske, Sebastian
• Fierke, Carol A.
• Getz, Gad
• Sunyaev, Shamil R.
• Wade Harper, J.
• Cichowski, Karen
• Kimmelman, Alec C.
• Houvras, Yariv
• Syngal, Sapna
• Williams, Carol
• Goessling, Wolfram

Titel

Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer

Ist Teil von

• Nature genetics, 2019-09, Vol.51 (9), p.1308-1314

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Pancreatic ductal adenocarcinoma is an aggressive cancer with limited treatment options 1 . Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families 2 . We perform whole-genome sequence analysis in a family with multiple cases of pancreatic ductal adenocarcinoma and identify a germline truncating mutation in the member of the RAS oncogene family-like 3 ( RABL3 ) gene. Heterozygous rabl3 mutant zebrafish show increased susceptibility to cancer formation. Transcriptomic and mass spectrometry approaches implicate RABL3 in RAS pathway regulation and identify an interaction with RAP1GDS1 (SmgGDS), a chaperone regulating prenylation of RAS GTPases 3 . Indeed, the truncated mutant RABL3 protein accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Finally, evidence in patient cohorts with developmental disorders implicates germline RABL3 mutations in RASopathy syndromes. Our studies identify RABL3 mutations as a target for genetic testing in cancer families and uncover a mechanism for dysregulated RAS activity in development and cancer. A mutation in RAS oncogene family-like 3 ( RABL3 ) is discovered in a family with multiple cases of pancreatic cancer. Zebrafish modeling and biochemical approaches suggest that truncated RABL3 elevates KRAS activity via accelerated prenylation.