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.
Tulpule, Asmin and Guan, Juan and Neel, Dana and Lin, Yone Phar and Heslin, Ann and Allegakoen, Hannah and Perati, Shriya and Ramirez, Alejandro D. and Shi, Xiaoyu and Yang, Bin and Feng, Siyu and Makhija, Suraj and Brown, David and Huang, Bo and Bivona, Trever, Kinase-Mediated RAS Signaling Via Membraneless Cytoplasmic Protein Granules. Available at SSRN: https://ssrn.com/abstract=3578156 or http://dx.doi.org/10.2139/ssrn.3578156
This version of the paper has not been formally peer reviewed.
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