l-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes

Abstract

In the present study, we examined the role in hematopoiesis of cationic amino acid transporter 1 (CAT1) , IntroductionCytokines such as interleukin-3 (IL-3) and erythropoietin play an important role in the differentiation of hematopoietic stem cells. 1,2 However, the roles of small molecules such as vitamins, nucleic acids, and amino acids in cell differentiation have not been elucidated well, though it is likely that specific transporters are involved in importing such small hydrophilic molecules into the cells. The ABC transporter Bcrp1 (abcg2) is expressed mainly in hematopoietic stem cells, 3 and more recently, efflux transporter activities in murine hematopoietic stem cells (HSCs) were found to vary according to developmental and activation status. 4 Thiamine transporter Thtr-1 (slc19a2) gene knockout mice showed abnormalities of erythroid, myeloid, and megakaryocyte lineages in bone marrow when fed a thiamine-free diet. 5 The importance of CAT1 (cationic amino acid transporter)-mediated transport was recently underscored by the production of cat1 gene knockout mice, which exhibit anemia. 6 These reports indicate that substrates of transporters expressed on hematopoietic stem cells are physiologically essential in differentiation or proliferation of the cells, or both, and the expression levels and activities of these transporters are likely to be regulated stage and lineage specifically.Cationic amino acid transporter (CAT, slc7a), known as system y ϩ , transports cationic amino acids such as L-lysine, L-histidine, L-ornithine, and L-arginine. 7-9 System y ϩ is a facilitative process that is Na ϩ -independent and pH insensitive. CAT1 (slc7a1), whose mouse ortholog was first identified as a virus receptor, 10,11 is expressed ubiquitously, including fetal liver and bone marrow, though not adult liver. 12 It is known that fetal and embryonic liver plays a significant role in hematopoiesis. 13 Furthermore, CAT1 mRNA is induced in regenerating liver in a short-lived manner and has multiple sites for regulation of gene expression, indicating that system y ϩ is tightly regulated and essential for liver cells to enter mitosis. 14,15 These findings suggest that CAT1 could be involved in hematopoietic activity.One of the substrates of CAT1, L-arginine, is a precursor of nitric oxide (NO) and polyamines. NO can induce apoptosis in megakaryocytes and platelet formation. 16,17 L-ornithine is produced by arginase and further metabolized to polyamines, which regulate the cell cycle. 18 Recently, low concentrations of L-glutamine were reported to induce functional differentiation of U937 myelomonocytic cells. 19 These facts suggest that low-molecular-weight molecules such as amino acids may be involved in hematopoiesis, as well as large-molecular cytokines such as IL-3 and erythropoietin. In the present study, we investigated the effects of hCAT1 expression level and L-arginine on differentiation and proliferation of human cord blood cells and a cloned human erythroid model, K562 cells. Materials and methods Tissue cultur...

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo

“…To test whether the increased uptake of arginine is because of the CAT-1, we inhibited CAT-1 using N-ethylmaleimide. 25 The CAT-1 inhibitor reduced the uptake of labeled arginine into sensitive but not resistant AML ( Figure 5E), consistent with increased uptake of arginine via CAT-1 in ADI-PEG 20-sensitive AMLs.…”

“…To test this we measured the uptake of labeled 13 C 6 arginine into AML cells. 25 Significantly more labeled arginine was found inside ADI-PEG 20-sensitive AMLs cells than inside resistant AML cells ( Figure 5E). To test whether the increased uptake of arginine is because of the CAT-1, we inhibited CAT-1 using N-ethylmaleimide.…”

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

“…The role of the CAT family of proteins in hematopoiesis has only received limited study, identifying CAT-1 and CAT-2B as the main transporters responsible for arginine uptake in in vitro models of nonmalignant myeloid and erythroid cells. [34][35][36] Arginine can be produced within healthy cells, by the ornithinecitrulline-arginine cycle. 37,38 We identified that the majority of patients' blasts are deficient in either ASS or OTC enzymes, strongly suggesting that AML blasts are reliant on extracellular arginine availability.…”

Maturing reticulocytes internalize plasma membrane in glycophorin A–containing vesicles that fuse with autophagosomes before exocytosis

“…Arginine import through the CAT1 and CD98hc transport systems is required for proliferation and differentiation of erythroid cells. 21,22 In contrast, some CD147 is retained in the mature erythrocyte, possibly to facilitate lactate transport through MCT1. We observe a gross reduction in expression of tubulin and loss of cytosolic actin as the human reticulocyte matured, as described previously in murine reticulocytes.…”