title: Sphingomyelin synthase 1-generated sphingomyelin plays an important role in transferrin trafficking and cell proliferation.
abstract: Transferrin (Tf) endocytosis and recycling are essential for iron uptake and the regulation of cell proliferation. Tf and Tf receptor (TfR) complexes are internalized via clathrin-coated pits composed of a variety of proteins and lipids and pass through early endosomes to recycling endosomes. We investigated the role of sphingomyelin (SM) synthases (SMS1 and SMS2) in clathrin-dependent trafficking of Tf and cell proliferation. We employed SM-deficient lymphoma cells that lacked SMSs and that failed to proliferate in response to Tf. Transfection of SMS1, but not SMS2, enabled these cells to incorporate SM into the plasma membrane, restoring Tf-mediated proliferation. SM-deficient cells showed a significant reduction in clathrin-dependent Tf uptake compared with the parental SM-producing cells. Both SMS1 gene transfection and exogenous short-chain SM treatment increased clathrin-dependent Tf uptake in SM-deficient cells, with the Tf being subsequently sorted to Rab11-positive recycling endosomes. We observed trafficking of the internalized Tf to late/endolysosomal compartments, and this was not dependent on the clathrin pathway in SM-deficient cells. Thus, SMS1-mediated SM synthesis directs Tf-TfR to undergo clathrin-dependent endocytosis and recycling, promoting the proliferation of lymphoma cells.
authors.affiliation: Division of Clinical Laboratory Medicine and Hematology/Oncology, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan.
authors.forename: Abo Bakr Abdel
authors.initials: ABA
authors.lastname: Shakor
authors.affiliation: Division of Clinical Laboratory Medicine and Hematology/Oncology, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Division of Clinical Laboratory Medicine and Hematology/Oncology, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kitatani
authors.affiliation: Division of Clinical Laboratory Medicine and Hematology/Oncology, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Division of Clinical Laboratory Medicine and Hematology/Oncology, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Asano
authors.affiliation: Division of Clinical Laboratory Medicine and Hematology/Oncology, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Division of Clinical Laboratory Medicine and Hematology/Oncology, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nomura
authors.affiliation: Departmant of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.affiliation: Departmant of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.affiliation: Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka-cho, Obu, Aichi 474-8511, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako 351-0198, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Sciences, Hokkaido University, Kita 21-jo, Nishi 11-choume, Kita-ku, Sapporo 001-0021, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.affiliation: Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku Uchinada, Ishikawa 902-0293, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Umehara
authors.affiliation: Division of Pathological Biochemistry, Department of Biomedical Science, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeya
authors.affiliation: Division of Clinical Laboratory Medicine and Hematology/Oncology, Faculty of Medicine, Tottori University, 86 Nishi-Cho, Yonago 683-8503, Japan; Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku Uchinada, Ishikawa 902-0293, Japan. Electronic address: toshiroo@kanazawa-med.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Okazaki
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003034:Coated Pits, Cell-Membrane / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000096:biosynthesis* / Q000235:genetics; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism*; D014168:Transferrin / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011990:Receptors, Transferrin; D013109:Sphingomyelins; D017855:Transferases (Other Substituted Phosphate Groups); D014168:Transferrin; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C455440:SGMS1 protein, human; C556686:Sgms1 protein, mouse