Spred-1 negatively regulates interleukin-3-mediated ERK/mitogen-activated protein (MAP) kinase activation in hematopoietic cells

J Biol Chem. 2004 Dec 10;279(50):52543-51. doi: 10.1074/jbc.M405189200. Epub 2004 Sep 30.

Abstract

Sprouty/Spred family proteins have been identified as negative regulators of growth factor-induced ERK/mitogen-activated protein (MAP) kinase activation. However, it has not been clarified whether these proteins regulate cytokine-induced ERK activity. We found that Spred-1 is highly expressed in interleukin-3 (IL-3)-dependent hematopoietic cell lines and bone marrow-derived mast cells. To investigate the roles of Spred-1 in hematopoiesis, we expressed wild-type Spred-1 and a dominant negative form of Spred-1, DeltaC-Spred, in IL-3- and stem cell factor (SCF)-dependent cell lines as well as hematopoietic progenitor cells from mouse bone marrow by retrovirus gene transfer. In IL-3-dependent Ba/F3 cells expressing c-kit, forced expression of Spred-1 resulted in a reduced proliferation rate and ERK activation in response to not only SCF but also IL-3. In contrast, DeltaC-Spred augmented IL-3-induced cell proliferation and ERK activation. Wild-type Spred-1 inhibited colony formation of bone marrow cells in the presence of cytokines, whereas DeltaC-Spred-1 expression enhanced colony formation. Augmentation of ERK activation and proliferation in response to IL-3 was also observed in Spred-1-deficient bone marrow-derived mast cells. These data suggest that Spred-1 negatively regulates hematopoiesis by suppressing not only SCF-induced but also IL-3-induced ERK activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Colony-Forming Units Assay
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression
  • Hematopoiesis
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • In Vitro Techniques
  • Interleukin-3 / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Stem Cell Factor / metabolism

Substances

  • Interleukin-3
  • Repressor Proteins
  • Spred1 protein, mouse
  • Stem Cell Factor
  • Extracellular Signal-Regulated MAP Kinases