Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia

J Clin Invest. 2013 Mar;123(3):1123-37. doi: 10.1172/JCI63711. Epub 2013 Feb 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Animals
  • Bone Marrow Cells / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Clathrin-Coated Vesicles / metabolism
  • Endocytosis
  • Kinetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Lysosomes / metabolism
  • Mast Cells / metabolism
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Myelodysplastic Syndromes / metabolism*
  • Protein Transport
  • Proto-Oncogene Proteins c-kit / metabolism
  • Signal Transduction
  • Spleen / pathology
  • Transferrin / metabolism

Substances

  • Membrane Proteins
  • SMAP2 protein, mouse
  • Smap1 protein, mouse
  • Transferrin
  • Proto-Oncogene Proteins c-kit
  • ADP-Ribosylation Factors
  • ADP-ribosylation factor 6