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Research Article
Acylpeptide hydrolase is a novel regulator of KRAS plasma membrane localization and function
Lingxiao Tan, Kwang-Jin Cho, Walaa E. Kattan, Christian M. Garrido, Yong Zhou, Pratik Neupane, Robert J. Capon, John F. Hancock
Journal of Cell Science 2019 132: jcs232132 doi: 10.1242/jcs.232132 Published 31 July 2019
Lingxiao Tan
Department of Integrative Biology and Pharmacology, McGovern Medical School University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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  • ORCID record for Lingxiao Tan
Kwang-Jin Cho
Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA
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Walaa E. Kattan
Department of Integrative Biology and Pharmacology, McGovern Medical School University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Christian M. Garrido
Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA
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Yong Zhou
Department of Integrative Biology and Pharmacology, McGovern Medical School University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Pratik Neupane
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia
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Robert J. Capon
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia
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John F. Hancock
Department of Integrative Biology and Pharmacology, McGovern Medical School University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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  • For correspondence: john.f.hancock@uth.tmc.edu
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ABSTRACT

The primary site for KRAS signaling is the inner leaflet of the plasma membrane (PM). We previously reported that oxanthroquinone G01 (G01) inhibited KRAS PM localization and blocked KRAS signaling. In this study, we identified acylpeptide hydrolase (APEH) as a molecular target of G01. APEH formed a stable complex with biotinylated G01, and the enzymatic activity of APEH was inhibited by G01. APEH knockdown caused profound mislocalization of KRAS and reduced clustering of KRAS that remained PM localized. APEH knockdown also disrupted the PM localization of phosphatidylserine (PtdSer), a lipid critical for KRAS PM binding and clustering. The mislocalization of KRAS was fully rescued by ectopic expression of APEH in knockdown cells. APEH knockdown disrupted the endocytic recycling of epidermal growth factor receptor and transferrin receptor, suggesting that abrogation of recycling endosome function was mechanistically linked to the loss of KRAS and PtdSer from the PM. APEH knockdown abrogated RAS–RAF–MAPK signaling in cells expressing the constitutively active (oncogenic) mutant of KRAS (KRASG12V), and selectively inhibited the proliferation of KRAS-transformed pancreatic cancer cells. Taken together, these results identify APEH as a novel drug target for a potential anti-KRAS therapeutic.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    Conceptualization: L.T., P.N., R.J.C., J.F.H.; Methodology: L.T., K.-J.C., W.E.K., C.M.G., Y.Z., P.N., R.J.C., J.F.H.; Software: L.T., K.-J.C., W.E.K., C.M.G., Y.Z., P.N., R.J.C., J.F.H.; Validation: L.T., K.-J.C., W.E.K., C.M.G., Y.Z., P.N., R.J.C., J.F.H.; Formal analysis: L.T., K.-J.C., W.E.K., C.M.G., Y.Z., P.N., R.J.C., J.F.H.; Investigation: L.T., K.-J.C., W.E.K., C.M.G., Y.Z., P.N., R.J.C., J.F.H.; Resources: L.T., K.-J.C., C.M.G., Y.Z., P.N., R.J.C., J.F.H.; Data curation: L.T., K.-J.C., Y.Z., J.F.H.; Writing - original draft: L.T., J.F.H.; Writing - review & editing: L.T., K.-J.C., W.E.K., C.M.G., P.N., R.J.C., J.F.H.; Visualization: L.T., Y.Z., P.N., R.J.C., J.F.H.; Supervision: L.T., K.-J.C., Y.Z., R.J.C., J.F.H.; Project administration: L.T., J.F.H.; Funding acquisition: J.F.H.

  • Funding

    This work was supported by grants from the Cancer Prevention and Research Institute of Texas (CPRIT; RP170233 to J.F.H.) and the National Cancer Institute (R00CA188593 to K.-J.C.). Deposited in PMC for release after 12 months.

  • Supplementary information

    Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.232132.supplemental

  • Received March 19, 2019.
  • Accepted June 18, 2019.
  • © 2019. Published by The Company of Biologists Ltd
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Keywords

  • KRAS
  • Acylpeptide hydrolase
  • Recycling endosome
  • Oxanthroquinone
  • Plasma membrane
  • Sphingomyelin metabolism

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Research Article
Acylpeptide hydrolase is a novel regulator of KRAS plasma membrane localization and function
Lingxiao Tan, Kwang-Jin Cho, Walaa E. Kattan, Christian M. Garrido, Yong Zhou, Pratik Neupane, Robert J. Capon, John F. Hancock
Journal of Cell Science 2019 132: jcs232132 doi: 10.1242/jcs.232132 Published 31 July 2019
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Research Article
Acylpeptide hydrolase is a novel regulator of KRAS plasma membrane localization and function
Lingxiao Tan, Kwang-Jin Cho, Walaa E. Kattan, Christian M. Garrido, Yong Zhou, Pratik Neupane, Robert J. Capon, John F. Hancock
Journal of Cell Science 2019 132: jcs232132 doi: 10.1242/jcs.232132 Published 31 July 2019

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