title: Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer.
abstract: Endosomal sorting complexes required for transport (ESCRT) drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3) drives tumorigenesis in vivo. Indeed, Ptpn23(+/-) loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23(+/-)-derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23(+/-) loss increases integrin β1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking.
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Manteghi
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kharitidi
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Galarneau
authors.affiliation: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada.
authors.forename: Maud
authors.initials: M
authors.lastname: Marques
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Robert
authors.affiliation: Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, QC J2S 2M2, Canada.
authors.forename: Marilène
authors.initials: M
authors.lastname: Paquet
authors.affiliation: Departments of Oncology and Experimental Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Witcher
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: arnim.pause@mcgill.ca.
authors.forename: Arnim
authors.initials: A
authors.lastname: Pause
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency / Q000235:genetics*; D057898:Hemizygote; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D016023:Integrins; D016271:Proto-Oncogene Proteins c-myc; C114102:PTPN23 protein, human; C584443:PTPN23 protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor