title: Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia.
abstract: The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking between subcellular compartments and is triggered by the ARF family of small GTPases. We previously identified SMAP1 as an ARF6 GTPase-activating protein that functions in clathrin-dependent endocytosis. Because abnormalities in clathrin-dependent trafficking are often associated with oncogenesis, we targeted Smap1 in mice to examine its physiological and pathological significance. Smap1-deficent mice exhibited healthy growth, but their erythroblasts showed enhanced transferrin endocytosis. In mast cells cultured in SCF, Smap1 deficiency did not affect the internalization of c-KIT but impaired the sorting of internalized c-KIT from multivesicular bodies to lysosomes, resulting in intracellular accumulation of undegraded c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, approximately 50% of aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are hematological abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, to our knowledge these results provide the first evidence in a mouse model that the deregulation of clathrin-dependent membrane trafficking may be involved in the development of MDS and subsequent AML.
authors: Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors: Shunsuke
authors: S
authors: Kon
authors: Naoko
authors: N
authors: Minegishi
authors: Kenji
authors: K
authors: Tanabe
authors: Toshio
authors: T
authors: Watanabe
authors: Tomo
authors: T
authors: Funaki
authors: Won Fen
authors: WF
authors: Wong
authors: Daisuke
authors: D
authors: Sakamoto
authors: Yudai
authors: Y
authors: Higuchi
authors: Hiroshi
authors: H
authors: Kiyonari
authors: Katsutoshi
authors: K
authors: Asano
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Manabu
authors: M
authors: Fukumoto
authors: Motomi
authors: M
authors: Osato
authors: Masashi
authors: M
authors: Sanada
authors: Seishi
authors: S
authors: Ogawa
authors: Takuro
authors: T
authors: Nakamura
authors: Masanobu
authors: M
authors: Satake
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000378:metabolism*; D021381:Protein Transport; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D014168:Transferrin / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; D008565:Membrane Proteins; C529588:SMAP2 protein, mouse; C484577:Smap1 protein, mouse; D014168:Transferrin; D019009:Proto-Oncogene Proteins c-kit; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse