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Ret receptor tyrosine kinase activates extracellular signal-regulated kinase 2 in SK-N-MC cells

D H van Weering1, J P Medema, A van Puijenbroek

  • 1Graduate School of Developmental Biology, Laboratory for Physiological Chemistry, Utrecht University, The Netherlands.

Oncogene
|December 7, 1995
PubMed

Insights

Ret receptor tyrosine kinase activation in neuroectodermal cells triggers downstream signaling, including extracellular signal-regulated kinase 2 (ERK2) activation, dependent on p21ras. This clarifies Ret

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Ret is a receptor tyrosine kinase implicated in neuroectodermal development and diseases like multiple endocrine neoplasia and Hirschsprung's disease.
  • Previous studies showed Ret activation leads to p21ras activation but not extracellular signal-regulated kinase 2 (ERK2) in fibroblasts.
  • The endogenous ligand for Ret remains unidentified.

Purpose of the Study:

  • To investigate early signaling events mediated by an activated human epidermal growth factor receptor-Ret (HERRet) fusion receptor in a neuroectodermal cell line (SK-N-MC).
  • To determine if Ret activation can induce ERK2 activation in cells where Ret is endogenously expressed.
  • To elucidate the role of p21ras in Ret-mediated signaling pathways.

Main Methods:

  • Utilized a HERRet fusion receptor stably transfected into SK-N-MC cells, a neuroectodermal cell line.
  • Analyzed tyrosine phosphorylation of Shc, complex formation of Shc with Grb2 and Sos, and p21ras activation.
  • Assessed ERK2 activation and its dependence on p21ras using a dominant-negative p21ras mutant (p21rasasn17).

Main Results:

  • Activated HERRet induced tyrosine phosphorylation of Shc, Shc-Grb2-Sos complex formation, and p21ras activation in SK-N-MC cells.
  • Importantly, ERK2 was strongly and sustainably activated for at least 2 hours.
  • ERK2 activation was completely abolished by the dominant-negative p21rasasn17 mutant, confirming p21ras-mediated signaling.

Conclusions:

  • Ret signaling in neuroectodermal cells, where it is endogenously expressed, can lead to ERK2 activation.
  • This ERK2 activation is dependent on the p21ras pathway.
  • These findings suggest a functional role for Ret in regulating p21ras-ERK2 signaling in relevant cellular contexts.

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