Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules
| Autor: | Siyu Feng, Asmin Tulpule, Alejandro Ramirez, Trever G. Bivona, David Brown, Hannah R. Allegakoen, Suraj Makhija, Bin Yang, Ann Heslin, Xiaoyu Shi, Juan Guan, Yone Phar Lin, Dana S. Neel, Shriya Perati, Bo Huang |
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| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
0303 health sciences Cell signaling biology Chemistry Kinase GTPase Receptor tyrosine kinase Cell biology 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis Mitogen-activated protein kinase biology.protein GRB2 Signal transduction 030304 developmental biology |
| Popis: | SummaryReceptor 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.HighlightsRTK oncoproteins can form de novo membraneless cytoplasmic protein granulesRTK protein granules activate RAS in lipid membrane-independent mannerHigher-order protein assembly is critical for oncogenic RAS/MAPK signalingProtein granules are a distinct subcellular platform for organizing RTK signaling |
| Databáze: | OpenAIRE |
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