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RET(MEN 2B) is active in the endoplasmic reticulum before reaching the cell surface

P Runeberg-Roos1, H Virtanen, M Saarma

  • 1Institute of Biotechnology, Viikki Biocenter, University of Helsinki, Helsinki, Finland. pia.runeberg@helsinki.fi

Oncogene
|June 30, 2007
PubMed

Insights

Multiple endocrine neoplasia type 2B (MEN 2B) involves an abnormal RET receptor tyrosine kinase. The MEN 2B precursor activates signaling pathways from the endoplasmic reticulum, even before reaching the cell surface.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant cancer syndrome.
  • It is caused by an oncogenic form of the REarranged during transfection (RET) receptor tyrosine kinase.
  • MEN 2B is characterized by abnormal, ligand-independent autophosphorylation of the mutated RET receptor.

Purpose of the Study:

  • To characterize the activation of the RET(MEN 2B) variant with the Met918Thr mutation.
  • To investigate the phosphorylation and signaling capabilities of the RET(MEN 2B) precursor in the endoplasmic reticulum (ER).

Main Methods:

  • Characterization of RET(MEN 2B) variant phosphorylation during synthesis in the ER.
  • Analysis of RET(MEN 2B) precursor interactions with adapter proteins (GRB2, SHC) in the ER.
  • Assessment of downstream signaling (AKT, ERK, STAT3) activation by ER-localized RET mutants.

Main Results:

  • The RET(MEN 2B) precursor is phosphorylated on multiple tyrosine residues (Tyr905, Tyr1062, Tyr1096) during synthesis in the ER.
  • The RET(MEN 2B) precursor interacts with GRB2 and SHC in the ER in a kinase activity-dependent manner.
  • ER-localized RET(MEN 2B) precursor activates AKT, ERK, and STAT3 signaling pathways.

Conclusions:

  • The oncogenic RET(MEN 2B) precursor is phosphorylated and interacts with adapter proteins within the ER.
  • Downstream signaling is initiated from the ER by the oncogenic RET(MEN 2B) precursor, preceding its cell surface arrival.

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