Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules

Abstract

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner to initiate MAPK signaling. Formation of membraneless protein granules by RTK oncoproteins is both necessary and sufficient for RAS/MAPK signaling output in cells. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform to activate RTKs and RAS GTPases and a general principle by which cells can organize oncogenic signaling. HighlightsO_LIRTK oncoproteins can form de novo membraneless cytoplasmic protein granules C_LIO_LIRTK protein granules activate RAS in lipid membrane-independent manner C_LIO_LIHigher-order protein assembly is critical for oncogenic RAS/MAPK signaling C_LIO_LIProtein granules are a distinct subcellular platform for organizing RTK signaling C_LI