Cell
Volume 184, Issue 10, 13 May 2021, Pages 2649-2664.e18
Journal home page for Cell

Article
Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules

https://doi.org/10.1016/j.cell.2021.03.031Get rights and content
Under a Creative Commons license
open access

Highlights

  • RTK oncoproteins can form de novo membraneless cytoplasmic protein granules

  • RTK protein granules activate RAS in a lipid membrane-independent manner

  • Higher-order protein assembly is critical for oncogenic RAS/MAPK signaling

  • Protein granules serve as a subcellular platform for organizing RTK signaling

Summary

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.

Keywords

RAS
receptor tyrosine kinase
MAPK
kinase
ALK
anaplastic lymphoma kinase
RET
biomolecular condensate
protein granule
gene fusion

Cited by (0)

9

These authors contributed equally

10

Lead contact