T-cell immunoglobulin and mucin domain 2 (TIM-2) is a target of ADAM10-mediated ectodomain shedding
Standard
T-cell immunoglobulin and mucin domain 2 (TIM-2) is a target of ADAM10-mediated ectodomain shedding. / Dewitz, Christin; Möller-Hackbarth, Katja; Schweigert, Olga; Reiss, Karina; Chalaris, Athena; Scheller, Jürgen; Rose-John, Stefan.
in: FEBS J, Jahrgang 281, Nr. 1, 01.2014, S. 157-74.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - T-cell immunoglobulin and mucin domain 2 (TIM-2) is a target of ADAM10-mediated ectodomain shedding
AU - Dewitz, Christin
AU - Möller-Hackbarth, Katja
AU - Schweigert, Olga
AU - Reiss, Karina
AU - Chalaris, Athena
AU - Scheller, Jürgen
AU - Rose-John, Stefan
N1 - © 2013 FEBS.
PY - 2014/1
Y1 - 2014/1
N2 - T-cell immunoglobulin and mucin domain (TIM)-2 is expressed on activated B cells. Here, we provide evidence that murine TIM-2 is a target of ADAM10-mediated ectodomain shedding, resulting in the generation of a soluble form of TIM-2. We identified ADAM10 but not ADAM17 as the major sheddase of TIM-2, as shown by pharmacological ADAM10 inhibition and with ADAM10-deficient and ADAM17-deficient murine embryonic fibroblasts. Ionomycin-induced or 2'(3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt-induced shedding of TIM-2 was abrogated by deletion of 10 juxtamembrane amino acids from the stalk region but not by deletion of two further N-terminally located blocks of 10 amino acids, indicating a membrane-proximal cleavage site. TIM-2 lacking the intracellular domain was cleaved after ionomycin or 2' (3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt treatment, indicating that this domain was not involved in the regulation of ectodomain shedding. Moreover, TIM-2 shedding was negatively controlled by calmodulin. Shed and soluble TIM-2 interacted with H-ferritin. In summary, we describe TIM-2 as a novel target for ADAM10-mediated ectodomain shedding, and reveal the involvement of ADAM proteases in cellular iron homeostasis.
AB - T-cell immunoglobulin and mucin domain (TIM)-2 is expressed on activated B cells. Here, we provide evidence that murine TIM-2 is a target of ADAM10-mediated ectodomain shedding, resulting in the generation of a soluble form of TIM-2. We identified ADAM10 but not ADAM17 as the major sheddase of TIM-2, as shown by pharmacological ADAM10 inhibition and with ADAM10-deficient and ADAM17-deficient murine embryonic fibroblasts. Ionomycin-induced or 2'(3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt-induced shedding of TIM-2 was abrogated by deletion of 10 juxtamembrane amino acids from the stalk region but not by deletion of two further N-terminally located blocks of 10 amino acids, indicating a membrane-proximal cleavage site. TIM-2 lacking the intracellular domain was cleaved after ionomycin or 2' (3')-O-(4-benzoylbenzoyl) ATP triethylammonium salt treatment, indicating that this domain was not involved in the regulation of ectodomain shedding. Moreover, TIM-2 shedding was negatively controlled by calmodulin. Shed and soluble TIM-2 interacted with H-ferritin. In summary, we describe TIM-2 as a novel target for ADAM10-mediated ectodomain shedding, and reveal the involvement of ADAM proteases in cellular iron homeostasis.
KW - ADAM Proteins/genetics
KW - ADAM10 Protein
KW - Amyloid Precursor Protein Secretases/genetics
KW - Animals
KW - Apoferritins/metabolism
KW - B-Lymphocytes/cytology
KW - Blotting, Western
KW - COS Cells
KW - Calmodulin/antagonists & inhibitors
KW - Cell Membrane/metabolism
KW - Cell Proliferation
KW - Cells, Cultured
KW - Chlorocebus aethiops
KW - Flow Cytometry
KW - HEK293 Cells
KW - Humans
KW - Immunoprecipitation
KW - Ionomycin/pharmacology
KW - Male
KW - Membrane Proteins/genetics
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mutation/genetics
U2 - 10.1111/febs.12583
DO - 10.1111/febs.12583
M3 - SCORING: Journal article
C2 - 24164679
VL - 281
SP - 157
EP - 174
JO - FEBS J
JF - FEBS J
SN - 1742-464X
IS - 1
ER -