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 that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling. READ ARTICLE
Cell DOI:10.1016/j.cell.2021.03.031
Authors: Asmin Tulpule, Juan Guan, Dana S Neel, Hannah R Allegakoen, Yone Phar Lin, David Brown, Yu-Ting Chou, Ann Heslin, Nilanjana Chatterjee, Shriya Perati, Shruti Menon, Tan A Nguyen, Jayanta Debnath, Alejandro D Ramirez, Xiaoyu Shi, Bin Yang, Siyu Feng, Suraj Makhija, Bo Huang, Trever G Bivona