Details

Autor(en) / Beteiligte

• 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

Titel

Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2024-05, Vol.121 (21), p.e2403685121

Ort / Verlag

United States

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• The 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. We then performed genome-wide CRISPR screens in spheroidal culture and found that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase. Finally, we used chemical inhibitors and a pH-sensitive reporter to determine that LKB1 impairs growth by promoting the internalization of wild-type EGFR in a PIKFYVE-dependent manner.