title: Latexin regulates the abundance of multiple cellular proteins in hematopoietic stem cells.
abstract: Latexin is the only known carboxypeptidase A inhibitor in mammals and shares structural similarity with cystatin C, suggesting that latexin regulates the abundance of as yet unidentified target proteins. A forward genetic approach revealed that latexin is involved in homeostasis of hematopoietic stem cells (HSCs) in mice; however, little is known about the mechanisms by which latexin negatively affects the numbers of HSCs. In this study, we found that latexin is preferentially expressed in hematopoietic stem/progenitor cells, and is co-localized with the molecules responsible for the interaction of HSCs with a bone marrow niche, such as N-cadherin, Tie2, and Roundabout 4. Latexin-knockout young female mice showed an increase in the numbers of KSL (c-Kit(+)/Sca-1(+)/linegae marker-negative) cells, which may be attributable to enhanced self-renewal because latexin-deficient KSL cells formed more colonies than their wild-type counterparts in methylcellulose culture. Proteomic analysis of Sca-1(+) bone marrow cells demonstrated that latexin ablation reduced the abundance of multiple cellular proteins, including N-cadherin, Tie2, and Roundabout 4. Finally, we found that latexin expression was lost or greatly reduced in approximately 50% of human leukemia/lymphoma cell lines. These results imply that latexin inhibits the self-renewal of HSCs by facilitating the lodgment of HSCs within a bone marrow niche to maintain HSC homeostasis.
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Mitsunaga
authors.forename: Jiro
authors.initials: J
authors.lastname: Kikuchi
authors.forename: Taeko
authors.initials: T
authors.lastname: Wada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000941:Antigens; C086812:Lxn protein, rat