The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes
Amanda K. Riley,
Michael Grant,
Aidan Snell,
Elizabeth Cromwell,
Athea Vichas,
Sitapriya Moorthi,
Callie Rominger,
Shrikar P. Modukuri,
Anatoly Urisman,
Pau Castel,
Lixin Wan,
Alice H. Berger
Affiliations
Amanda K. Riley
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA
Michael Grant
Department of Molecular Oncology, Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
Aidan Snell
Department of Molecular Oncology, Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
Elizabeth Cromwell
Preclinical Modeling Shared Resource, Fred Hutch Cancer Center, Seattle, WA, USA
Athea Vichas
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
Sitapriya Moorthi
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
Callie Rominger
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
Shrikar P. Modukuri
Department of Molecular Oncology, Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; Department of Chemistry, University of South Florida, Tampa, FL, USA
Anatoly Urisman
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
Pau Castel
Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
Lixin Wan
Department of Molecular Oncology, Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; Corresponding author
Alice H. Berger
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Herbold Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA; Corresponding author
Summary: RIT1 is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function. We previously identified the deubiquitinase USP9X as a RIT1 dependency in RIT1-mutant cells. Here, we demonstrate that both wild-type and mutant forms of RIT1 are substrates of USP9X. Depletion of USP9X leads to decreased RIT1 protein stability and abundance and resensitizes cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in vitro and in vivo. Our work expands upon the current understanding of RIT1 protein regulation and presents USP9X as a key regulator of RIT1-driven oncogenic phenotypes.
