Cited by 189Protein Kinase Regulation and GTPase SignalingRNA Research and SplicingCellular transport and secretion

Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules

Open access
Tulpule, Asmin, Guan, Juan, Neel, Dana S., Allegakoen, Hannah R., Lin, Yone Phar, Brown, David, Chou, Yu-Ting, Heslin, Ann +12 more·2021·Cell

Published version of a preprint

Abstract

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.

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Crossref · 10.1016/j.cell.2021.03.031

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  • The intracellular EML4-ALK fusion protein recruits RTK adaptor proteins, resulting in the elicitation of cytoplasmic KRAS localization.

    “Related to this, the intracellular EML4-ALK fusion protein has been shown to recruit RTK adaptor proteins, resulting in the elicitation of cytoplasmic KRAS localization47.”

    From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [47]

    The Results section on GRB2/SOS1/GAB1 recruitment reports that EML4-ALK granules recruit RTK adaptor proteins. The Results section on local RAS activation reports activation of a cytosolic KRAS mutant and enrichment of a RAS-GTP reporter at the granules, but it describes a pre-existing cytosolic RAS pool—not EML4-ALK causing KRAS to relocate to the cytoplasm. Page numbers are not available in our copy. (LLM, conf=0.87)

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Authors
Tulpule, A., Guan, J., Neel, D. S., Allegakoen, H. R., Lin, Y. P., Brown, D., Chou, Y.-T., Heslin, A., Chatterjee, N., Perati, S., Menon, S., Nguyen, T. A., Debnath, J., Ramirez, A. D., Shi, X., Yang, B., Feng, S., Makhija, S., Huang, B., & Bivona, T. G.
Affiliations
University of California, San Francisco (US)
Corresponding author
  • Huang, Bo
  • Bivona, Trever G.
Venue
Cell
Publisher
Elsevier BV
Published
2021-05
Volume
184
Issue
10
Pages
2649-2664.e18
ISSN
0092-8674 (ISSN-L)
OpenAlex
W3155633297
Cited by
189
References
67
Citations by year
2026: 25 · 2025: 35 · 2024: 36 · 2023: 46 · 2022: 27 · 2021: 18 · 2020: 2
FWCI
7.54
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion, cc-by)
  • SSRN Electronic Journal (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • NIH
  • NCI Cancer Moonshot
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
biomolecular condensates, receptor tyrosine kinase, RAS/MAPK pathway, anaplastic lymphoma kinase, RET, fusion oncoproteins, cancer signaling
MeSH terms
Biomolecular Condensates, Cytoplasmic Granules, Enzyme Activation, Humans, Neoplasms, Signal Transduction, Oncogene Proteins, Fusion, ras Proteins, SOS1 Protein, Adaptor Proteins, Signal Transducing, GRB2 Adaptor Protein, HEK293 Cells

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