hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

Cell Signal. 2008 Mar;20(3):518-33. doi: 10.1016/j.cellsig.2007.11.010. Epub 2007 Nov 28.


Sef (similar expression to fgf genes) was identified as an effective antagonist of fibroblast growth factor (FGF) in vertebrates. Previous reports have demonstrated that Sef interacts with FGF receptors (FGFRs) and inhibits FGF signaling, however, its role in regulating epidermal growth factor receptor (EGFR) signaling remains unclear. In this report, we found that hSef localizes to the plasma membrane (PM) and is subjected to rapid internalization and well localizes in early/recycling endosomes while poorly in late endosomes/lysosomes. We observed that hSef interacts and functionally colocalizes with EGFR in early endosomes in response to EGF stimulation. Importantly, we demonstrated that overexpression of hSef attenuates EGFR degradation and potentiates EGF-mediated mitogen-activated protein kinase (MAPK) signaling by interfering EGFR trafficking. Finally, our data showed that, with overexpression of hSef, elevated levels of Erk phosphorylation and differentiation of rat pheochromocytoma (PC12) cells occur in response to EGF stimulation. Taken together, these data suggest that hSef plays a positive role in the EGFR-mediated MAPK signaling pathway. This report, for the first time, reveals opposite roles for Sef in EGF and FGF signalings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Differentiation
  • Cell Membrane / metabolism*
  • Chlorocebus aethiops
  • Endocytosis
  • Endosomes / metabolism*
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblast Growth Factor 2 / metabolism
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurites / enzymology
  • Neurites / metabolism
  • Neurons / enzymology
  • Neurons / metabolism
  • PC12 Cells
  • Phosphorylation
  • Protein Transport
  • Rats
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism*
  • Time Factors
  • Transfection


  • IL17RD protein, human
  • Receptors, Interleukin
  • Fibroblast Growth Factor 2
  • Epidermal Growth Factor
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases