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Cytoplasmic protein granules organize kinase-mediated RAS signaling

Asmin Tulpule, Juan Guan, Dana S. Neel, Yone Phar Lin, Ann Heslin, Hannah Allegakoan, Shriya Perati, Alejandro D. Ramirez, Xiaoyu Shi, Bin Yang, Siyu Feng, View ORCID ProfileBo Huang, View ORCID ProfileTrever G. Bivona
doi: https://doi.org/10.1101/704312
Asmin Tulpule
Division of Pediatric Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
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Juan Guan
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA
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Dana S. Neel
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
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Yone Phar Lin
Division of Pediatric Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
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Ann Heslin
Division of Pediatric Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
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Hannah Allegakoan
Division of Pediatric Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
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Shriya Perati
Division of Pediatric Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
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Alejandro D. Ramirez
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA
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Xiaoyu Shi
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA
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Bin Yang
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA
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Siyu Feng
UC Berkeley – UCSF Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94143, USA
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Bo Huang
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USADepartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USAChan Zuckerberg Biohub, San Francisco, CA 94158, USA
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  • ORCID record for Bo Huang
  • For correspondence: trever.bivona@ucsf.edu bo.huang@ucsf.edu
Trever G. Bivona
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
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  • ORCID record for Trever G. Bivona
  • For correspondence: trever.bivona@ucsf.edu bo.huang@ucsf.edu
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Abstract

Understanding how cells spatially organize signaling events is important in normal biology and pathological conditions such as cancer. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize receptor tyrosine kinase (RTK)-mediated RAS/MAPK pathway signaling, which is thought to occur exclusively from lipid-membrane compartments in mammalian cells. De-novo assembly of cytoplasmic protein granules by certain RTKs, including oncogenic gene fusions involving ALK and RET, is dependent on multimerization domains in the RTK fusion partners. Protein granule formation is both necessary and sufficient to locally concentrate the RAS activating complex GRB2/SOS1 to initiate MAPK pathway signaling. Our findings reveal membraneless, higher-order protein assembly as a principle by which cells can organize kinase-mediated proliferative signals.

One Sentence Summary Kinase/RAS signaling via protein granules

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Posted July 16, 2019.
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Cytoplasmic protein granules organize kinase-mediated RAS signaling
Asmin Tulpule, Juan Guan, Dana S. Neel, Yone Phar Lin, Ann Heslin, Hannah Allegakoan, Shriya Perati, Alejandro D. Ramirez, Xiaoyu Shi, Bin Yang, Siyu Feng, Bo Huang, Trever G. Bivona
bioRxiv 704312; doi: https://doi.org/10.1101/704312
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Cytoplasmic protein granules organize kinase-mediated RAS signaling
Asmin Tulpule, Juan Guan, Dana S. Neel, Yone Phar Lin, Ann Heslin, Hannah Allegakoan, Shriya Perati, Alejandro D. Ramirez, Xiaoyu Shi, Bin Yang, Siyu Feng, Bo Huang, Trever G. Bivona
bioRxiv 704312; doi: https://doi.org/10.1101/704312

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