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Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia
Shunsuke Kon, … , Takuro Nakamura, Masanobu Satake
Shunsuke Kon, … , Takuro Nakamura, Masanobu Satake
Published February 22, 2013
Citation Information: J Clin Invest. 2013;123(3):1123-1137. https://doi.org/10.1172/JCI63711.
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Research Article Hematology Article has an altmetric score of 11

Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia

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Abstract

The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking between subcellular compartments and is triggered by the ARF family of small GTPases. We previously identified SMAP1 as an ARF6 GTPase-activating protein that functions in clathrin-dependent endocytosis. Because abnormalities in clathrin-dependent trafficking are often associated with oncogenesis, we targeted Smap1 in mice to examine its physiological and pathological significance. Smap1-deficent mice exhibited healthy growth, but their erythroblasts showed enhanced transferrin endocytosis. In mast cells cultured in SCF, Smap1 deficiency did not affect the internalization of c-KIT but impaired the sorting of internalized c-KIT from multivesicular bodies to lysosomes, resulting in intracellular accumulation of undegraded c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, approximately 50% of aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are hematological abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, to our knowledge these results provide the first evidence in a mouse model that the deregulation of clathrin-dependent membrane trafficking may be involved in the development of MDS and subsequent AML.

Authors

Shunsuke Kon, Naoko Minegishi, Kenji Tanabe, Toshio Watanabe, Tomo Funaki, Won Fen Wong, Daisuke Sakamoto, Yudai Higuchi, Hiroshi Kiyonari, Katsutoshi Asano, Yoichiro Iwakura, Manabu Fukumoto, Motomi Osato, Masashi Sanada, Seishi Ogawa, Takuro Nakamura, Masanobu Satake

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Figure 4

Transport kinetics and c-KIT signaling in BMMCs.

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Transport kinetics and c-KIT signaling in BMMCs.
(A) Endocytosis of c-KI...
(A) Endocytosis of c-KIT. Smap1+/+ and Smap1–/– BMMCs were cultured, starved in the presence of cycloheximide, incubated with SCF at 37°C for the indicated times, and processed for flow cytometry analyses. The top panel displays the fluorescence intensity of c-KIT and cell numbers, whereas the bottom panel plots the percentages of internalized c-KIT calculated by considering the initial surface fluorescence to be 100%. BMMCs were prepared from 3 independent pairs of Smap1+/+ and Smap1–/– mice and processed for assays. Averages ± SD of internalized c-KIT were calculated for each incubation time (n = 3). (B) Immunofluorescence detection of c-KIT in BMMCs. The Smap1+/+ and Smap1–/– cells were incubated in the presence of SCF for the indicated times and stained for c-KIT. Scale bar: 10 μm. (C) Activation status of c-KIT signaling molecules. Wild-type and Smap1–/– BMMCs were incubated with SCF for the indicated times, and protein lysates were prepared and processed for immunoprecipitation/immunoblot analyses. Band densities were quantified, and averages ± SD are shown (n = 3). p-c-KIT, phosphorylated form of c-KIT; p-ERK1/2, phosphorylated form of ERK1/2; ub-c-KIT, ubiquitinylated c-KIT; c-KIT-associated Grb2, Grb2 recruited into anti–c-KIT immunoprecipitates. (D) DNA synthesis in BMMCs. Triplicate cultures of cells were prepared from each of the wild-type and Smap1–/– mice, incubated in the presence of IL-3 and/or SCF for 16 hours, and then treated with 3H-thymidine for 8 hours. The incorporation of 3H-thymidine into acid-insoluble fractions was measured, and averages ± SD are shown (n = 3). *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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