T‐cell immunoglobulin and mucin domain 2 ( TIM ‐2) is a target of ADAM 10‐mediated ectodomain shedding

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 ADAM 10‐mediated ectodomain shedding, resulting in the generation of a soluble form of TIM ‐2. We identified ADAM 10 but not ADAM 17 as the major sheddase of TIM ‐2, as shown by pharmacological ADAM 10 inhibition and with ADAM 10‐deficient and ADAM 17‐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 ADAM 10‐mediated ectodomain shedding, and reveal the involvement of ADAM proteases in cellular iron homeostasis.