Understanding how cells spatially organize signaling events is important in normal biology and pathological conditions such as cancer. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize receptor tyrosine kinase (RTK)-mediated RAS/MAPK pathway signaling, which is thought to occur exclusively from lipid-membrane compartments in mammalian cells. De-novo assembly of cytoplasmic protein granules by certain RTKs, including oncogenic gene fusions involving

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... K and RET, is dependent on multimerization domains in the RTK fusion partners. Protein granule formation is both necessary and sufficient to locally concentrate the RAS activating complex GRB2/SOS1 to initiate MAPK pathway signaling. Our findings reveal membraneless, higher-order protein assembly as a principle by which cells can organize kinase-mediated proliferative signals.