TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis

Veterans Administration Medical Center, San Francisco, CA 94121, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 11/2005; 202(7):955-65. DOI: 10.1084/jem.20042433
Source: PubMed


T cell immunoglobulin-domain and mucin-domain (TIM) proteins constitute a receptor family that was identified first on kidney and liver cells; recently it was also shown to be expressed on T cells. TIM-1 and -3 receptors denote different subsets of T cells and have distinct regulatory effects on T cell function. Ferritin is a spherical protein complex that is formed by 24 subunits of H- and L-ferritin. Ferritin stores iron atoms intracellularly, but it also circulates. H-ferritin, but not L-ferritin, shows saturable binding to subsets of human T and B cells, and its expression is increased in response to inflammation. We demonstrate that mouse TIM-2 is expressed on all splenic B cells, with increased levels on germinal center B cells. TIM-2 also is expressed in the liver, especially in bile duct epithelial cells, and in renal tubule cells. We further demonstrate that TIM-2 is a receptor for H-ferritin, but not for L-ferritin, and expression of TIM-2 permits the cellular uptake of H-ferritin into endosomes. This is the first identification of a receptor for ferritin and reveals a new role for TIM-2.

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    • "The coding sequences of the two proteins were separated by an E2Asequence, which results in equimolar expression from the same transcript [42] (see Figure S1). Human embryonic kidney (HEK 293T) cells stably expressing a luciferase-YFP fusion protein [36], were transduced, at a multiplicity of infection of 2, with LV-PGK-SO, or with a control lentivirus, LV-PGK-ST, in which the coding sequence for Oatp1 was replaced with that of Timd2 [43]. Timd2 is a receptor that mediates H-ferritin endocytosis, and like Oatp1, is expressed on the plasma membrane in liver and kidney cells. "
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    ABSTRACT: Bioluminescence imaging is a powerful tool for studying gene expression and cell migration in intact living organisms. However, production of bioluminescence by cells transfected to express luciferase can be limited by the rate of plasma membrane transport of its substrate D-luciferin. We sought to identify a plasma membrane transporter for D-luciferin that could be expressed alongside luciferase to increase transmembrane flux of its substrate and thereby increase light output. Luciferase-expressing cells were transfected with a lentivirus encoding the rat reno-hepatic organic anion transporter protein, Oatp1, which was identified as a potential transporter for D-luciferin. Light output was compared between cells expressing luciferase and those also expressing Oatp1. In two cell lines and in mouse xenografts, co-expression of Oatp1 with luciferase increased light output by several fold, following addition of luciferin. The increase in light output thus obtained will allow more sensitive detection of luciferase-expressing cells in vivo.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 05/2014; 16(5). DOI:10.1007/s11307-014-0741-4 · 2.77 Impact Factor
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    • "Additionally, the TIM-2 knockout murine model displays an exacerbated Th-2-driven response in a model of ovalbumin-induced airway inflammation.7 Semaphorin-4A is a recognized TIM-2 ligand,79 yet semaphorin-4A-deficient mice develop exaggerated Th-2 phenotypes, supporting TIM-2 as an inhibitor of Th-2 responses.80 TIM-2 was also identified as a specific heavy chain ferritin (H-ferritin) receptor leading to endocytosis of extracellular H-ferritin in liver81 and brain.82 H-ferritin has been reported to display immunological properties, mainly as a regulator of proliferation and differentiation of immune cells.83 "
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    ABSTRACT: T cell immunoglobulin and mucin-domain (TIM)-containing molecules have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. Despite the initial discovery linking TIM-containing molecules and the airway hyperreactivity regulatory locus in mice, there is a paucity of studies on the function of TIM-containing molecules in lung inflammatory disease. Initially, studies were limited to mice models of asthma. More recently however, TIM-containing molecules have been implicated in an ever-expanding list of airway conditions that includes pneumonia, tuberculosis, influenza, sarcoidosis, lung cancer, and cystic fibrosis. This present review discusses the role of TIM-containing molecules and their ligands in the lung, as well as their potential as therapeutic targets in airway disease.
    Journal of Inflammation Research 08/2012; 5(1):77-87. DOI:10.2147/JIR.S34225
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    • "Serum ferritin is elevated not only in conditions of iron overload, but in acute and chronic inflammation and cancer. Extracellular ferritin binds to cell surface receptors on mouse [16] and human [17] cells, and has been reported to exert a pro-inflammatory effect on hepatic stellate cells [18]. "
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    ABSTRACT: Angiogenesis is tightly regulated through complex crosstalk between pro- and anti-angiogenic signals. High molecular weight kininogen (HK) is an endogenous protein that is proteolytically cleaved in plasma and on endothelial cell surfaces to HKa, an anti-angiogenic protein. Ferritin binds to HKa and blocks its anti-angiogenic activity. Here, we explore mechanisms underlying the cytoprotective effect of ferritin in endothelial cells exposed to HKa. We observe that ferritin promotes adhesion and survival of HKa-treated cells and restores key survival and adhesion signaling pathways mediated by Erk, Akt, FAK and paxillin. We further elucidate structural motifs of both HKa and ferritin that are required for effects on endothelial cells. We identify an histidine-glycine-lysine (HGK) -rich antiproliferative region within domain 5 of HK as the target of ferritin, and demonstrate that both ferritin subunits of the H and L type regulate HKa activity. We further demonstrate that ferritin reduces binding of HKa to endothelial cells and restores the association of uPAR with α5β1 integrin. We propose that ferritin blocks the anti-angiogenic activity of HKa by reducing binding of HKa to UPAR and interfering with anti-adhesive and anti-proliferative signaling of HKa.
    PLoS ONE 07/2012; 7(7):e40030. DOI:10.1371/journal.pone.0040030 · 3.23 Impact Factor
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