Abstract
Oncogenic receptor tyrosine kinase fusions assembled into functional cytoplasmic protein granules.
Major Finding: Oncogenic receptor tyrosine kinase fusions assembled into functional cytoplasmic protein granules.
Concept: These granules, lacking membranes and RNA, activated the RAS pathway and other signaling pathways.
Impact: This suggests the existence of an alternate, membrane-free platform that can initiate RAS signaling.
Although it is generally accepted that activation of receptor tyrosine kinase (RTK) RAS-family GTPases and the consequent downstream MAPK signaling requires RTK and RAS protein association with a lipid membrane, recent studies have demonstrated that the fusion oncoprotein EML4–ALK, a chimera of the ALK (an RTK) kinase domain with a fragment of the protein EML4, is not found at the plasma membrane but instead exists in cytoplasmic structures of unknown identity. In light of these findings, Tulpule, Guan, Neel, and colleagues sought to better understand the nature of these structures and determine how EML4–ALK can activate oncogenic RAS signaling, potentially without membrane association. Experiments using the most common oncogenic EML4–ALK fusion protein (variant 1) in human cancers revealed the presence of EML4–ALK in protein-based cytoplasmic granules lacking RNA and lipid membranes and unperturbed by membrane-solubilizing agents, and although these granules were heterogeneous in biophysical nature, most exhibited solid-like properties. Further analysis showed that these EML4–ALK granules were capable of recruiting the RAS-activating ternary complex GRB2–SOS1–GAB1, which locally activated RAS proteins. Not only were these protein granules sufficient to activate downstream RAS signaling, but their formation was also necessary for EML4–ALK-mediated RAS signaling. Further, the formation of large, higher-order EML4–ALK-containing protein granules was essential for RAS–MAPK pathway activation in this context, whereas the presence of smaller multimers was not sufficient. Deeper investigation using additional RTKs suggested that signaling via membraneless protein granules may be a generalizable means of oncogenic chimeric RTK–driven RAS pathway activation distinct from known pathways involving membrane-associated RAS proteins. Collectively, these findings imply that phase-separated protein granules may underlie a unique mechanism of oncogenic RTK and RAS pathway activation, both common cancer drivers.
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