title: Rab14 and its exchange factor FAM116 link endocytic recycling and adherens junction stability in migrating cells.
abstract: Rab GTPases define the vesicle trafficking pathways underpinning cell polarization and migration. Here, we find that Rab4, Rab11, and Rab14 and the candidate Rab GDP-GTP exchange factors (GEFs) FAM116A and AVL9 are required for cell migration. Rab14 and its GEF FAM116A localize to and act on an intermediate compartment of the transferrin-recycling pathway prior to Rab11 and after Rab5 and Rab4. This Rab14 intermediate recycling compartment has specific functions in migrating cells discrete from early and recycling endosomes. Rab14-depleted cells show increased N-cadherin levels at junctional complexes and cannot resolve cell-cell junctions. This is due to decreased shedding of cell-surface N-cadherin by the ADAM family protease ADAM10/Kuzbanian. In FAM116A- and Rab14-depleted cells, ADAM10 accumulates in a transferrin-positive endocytic compartment, and the cell-surface level of ADAM10 is correspondingly reduced. FAM116 and Rab14 therefore define an endocytic recycling pathway needed for ADAM protease trafficking and regulation of cell-cell junctions.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Linford
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Ricardo
authors.initials: R
authors.lastname: Nunes Bastos
authors.forename: Lars
authors.initials: L
authors.lastname: Langemeyer
authors.forename: Andreas
authors.initials: A
authors.lastname: Gerondopoulos
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rigden
authors.forename: Francis A
authors.initials: FA
authors.lastname: Barr
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D022005:Adherens Junctions / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D001692:Biological Transport; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement; D011992:Endosomes / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D014168:Transferrin / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D020695:rab4 GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D015820:Cadherins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D014168:Transferrin; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D020695:rab4 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C573940:DENND6A protein, human; C491236:ADAM10 protein, human; C553411:Rab14 protein, human