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Kinase-Mediated RAS Signaling Via Membraneless Cytoplasmic Protein Granules

48 Pages Posted: 5 May 2020 Sneak Peek Status: Review Complete

See all articles by Asmin Tulpule

Asmin Tulpule

University of California, San Francisco (UCSF)

Juan Guan

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

Dana Neel

University of California, San Francisco (UCSF) - Division of Hematology/Oncology

Yone Phar Lin

University of California, San Francisco (UCSF)

Ann Heslin

University of California, San Francisco (UCSF)

Hannah Allegakoen

University of California, San Francisco (UCSF)

Shriya Perati

University of California, San Francisco (UCSF)

Alejandro D. Ramirez

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

Xiaoyu Shi

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

Bin Yang

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

Siyu Feng

University of California, San Francisco (UCSF) - UC Berkeley-UC San Francisco Graduate Program in Bioengineering

Suraj Makhija

University of California, San Francisco (UCSF) - UC Berkeley-UC San Francisco Graduate Program in Bioengineering

David Brown

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

Bo Huang

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

Trever Bivona

University of California, San Francisco (UCSF) - Division of Hematology/Oncology

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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. 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.

Keywords: receptor tyrosine kinase signaling, RTK, RAS, cancer signaling, protein granule, biomolecular condensate, kinase fusion oncoproteins, RTK fusions, ALK, anaplastic lymphoma kinase, RET, subcellular compartmentalization

Suggested Citation

Tulpule, Asmin and Guan, Juan and Neel, Dana and Lin, Yone Phar and Heslin, Ann and Allegakoen, Hannah and Perati, Shriya and Ramirez, Alejandro D. and Shi, Xiaoyu and Yang, Bin and Feng, Siyu and Makhija, Suraj and Brown, David and Huang, Bo and Bivona, Trever, Kinase-Mediated RAS Signaling Via Membraneless Cytoplasmic Protein Granules. Available at SSRN: https://ssrn.com/abstract=3578156 or http://dx.doi.org/10.2139/ssrn.3578156
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Asmin Tulpule

University of California, San Francisco (UCSF) ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Juan Guan

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry ( email )

San Francisco, CA 94143-2280
United States

Dana Neel

University of California, San Francisco (UCSF) - Division of Hematology/Oncology ( email )

San Francisco, CA 94143
United States

Yone Phar Lin

University of California, San Francisco (UCSF) ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Ann Heslin

University of California, San Francisco (UCSF)

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Hannah Allegakoen

University of California, San Francisco (UCSF) ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Shriya Perati

University of California, San Francisco (UCSF)

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Alejandro D. Ramirez

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

San Francisco, CA 94143-2280
United States

Xiaoyu Shi

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

San Francisco, CA 94143-2280
United States

Bin Yang

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

San Francisco, CA 94143-2280
United States

Siyu Feng

University of California, San Francisco (UCSF) - UC Berkeley-UC San Francisco Graduate Program in Bioengineering

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Suraj Makhija

University of California, San Francisco (UCSF) - UC Berkeley-UC San Francisco Graduate Program in Bioengineering ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

David Brown

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry

San Francisco, CA 94143-2280
United States

Bo Huang

University of California, San Francisco (UCSF) - Department of Pharmaceutical Chemistry ( email )

San Francisco, CA 94143-2280
United States

Trever Bivona (Contact Author)

University of California, San Francisco (UCSF) - Division of Hematology/Oncology ( email )

San Francisco, CA 94143
United States

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