Author:
Ferrarone John R.,Thomas Jerin,Unni Arun M.,Zheng Yuxiang,Nagiec Michal J.,Gardner Eric E.,Mashadova Oksana,Li Kate,Koundouros Nikos,Montalbano Antonino,Mustafa Meer,Cantley Lewis C.,Blenis John,Sanjana Neville E.,Varmus Harold
Abstract
SUMMARYThe tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1- mediated growth suppression we developed a spheroid-based cell culture assay to study LKB1- dependent growth. Using this assay, along with genome-wide CRISPR screens and validation with orthogonal methods, we discovered that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase, which promotes the internalization of wild-type EGFR. Our findings reveal a new mechanism of regulation of EGFR, which may have implications for the treatment ofLKB1-mutant LUAD.
Publisher
Cold Spring Harbor Laboratory