title: Interplay of Endosomal pH and Ligand Occupancy in Integrin α5β1 Ubiquitination, Endocytic Sorting, and Cell Migration.
abstract: Membrane trafficking of integrins plays a pivotal role in cell proliferation and migration. How endocytosed integrins are targeted either for recycling or lysosomal delivery is not fully understood. Here, we show that fibronectin (FN) binding to α5β1 integrin triggers ubiquitination and internalization of the receptor complex. Acidification facilitates FN dissociation from integrin α5β1 in vitro and in early endosomes, promoting receptor complex deubiquitination by the USP9x and recycling to the cell surface. Depending on residual ligand occupancy of receptors, some α5β1 integrins remain ubiquitinated and are captured by ESCRT-0/I, containing histidine domain-containing protein tyrosine phosphatase (HD-PTP) and ubiquitin-associated protein 1 (UBAP1), and are directed for lysosomal proteolysis, limiting receptor downstream signaling and cell migration. Thus, HD-PTP or UBAP1 depletion confers a pro-invasive phenotype. Thus, pH-dependent FN-integrin dissociation and deubiquitination of the activated integrin α5β1 are required for receptor resensitization and cell migration, representing potential targets to modulate tumor invasiveness.
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Canada, H3G 1Y6.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kharitidi
authors.affiliation: Department of Physiology and Research Group Focused on Protein Structure, McGill University, Montreal, Canada, H3G 1Y6.
authors.forename: Pirjo M
authors.initials: PM
authors.lastname: Apaja
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Canada, H3G 1Y6.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Manteghi
authors.affiliation: Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Canada, H3G 1Y6.
authors.forename: Elena
authors.initials: E
authors.lastname: Malitskaya
authors.affiliation: Department of Physiology and Research Group Focused on Protein Structure, McGill University, Montreal, Canada, H3G 1Y6.
authors.forename: Ariel
authors.initials: A
authors.lastname: Roldan
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Canada, H3G 1Y6.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.affiliation: Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Takagi
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Canada, H3G 1Y6; Department of Physiology and Research Group Focused on Protein Structure, McGill University, Montreal, Canada, H3G 1Y6. Electronic address: gergely.lukacs@mcgill.ca.
authors.forename: Gergely L
authors.initials: GL
authors.lastname: Lukacs
authors.affiliation: Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Canada, H3G 1Y6. Electronic address: arnim.pause@mcgill.ca.
authors.forename: Arnim
authors.initials: A
authors.lastname: Pause
mesh_terms: D000818:Animals; D016466:CHO Cells; D002465:Cell Movement; D006224:Cricetinae; D003412:Cricetulus; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D039081:Integrin alpha5beta1