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Shc and Enigma are both required for mitogenic signaling by Ret/ptc2
K Durick1, G N Gill, S S Taylor
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093-0654, USA.
Molecular and Cellular Biology
|April 7, 1998
Summary
Ret/ptc2, an oncogenic form of c-Ret receptor tyrosine kinase, requires Shc and Enigma for mitogenic signaling. Dimerization of Ret/ptc2 enables localized signaling complexes, driving cell proliferation in papillary thyroid carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Ret/ptc2 is an oncogenic, constitutively active form of the c-Ret receptor tyrosine kinase.
- Papillary thyroid carcinoma (PTC) often involves Ret rearrangements, leading to oncogenic Ret/ptc fusions.
Purpose of the Study:
- To investigate the molecular mechanisms underlying Ret/ptc2-mediated mitogenic signaling.
- To identify the specific proteins and interactions required for Ret/ptc2 activation and localization.
Main Methods:
- Coexpression of Ret/ptc2 with dominant-negative Ras and Raf.
- Analysis of Ret/ptc2 subcellular localization and its interaction with Enigma.
- Investigation of Ret/ptc2 interaction with Shc and subsequent Shc phosphorylation.
- Coexpression of chimeric proteins to dissect signaling pathways.
Main Results:
- Mitogenic signaling by Ret/ptc2 is dependent on Ras and Raf.
- Ret/ptc2 localizes to the cell periphery via Enigma, specifically through tyrosine 586.
- Shc interacts with Ret/ptc2 at tyrosine 586, leading to Shc phosphorylation.
- Both Shc recruitment and Enigma-mediated localization are essential for Ret/ptc2 mitogenic activity.
Conclusions:
- Ret/ptc2 signaling requires both Shc recruitment and Enigma-mediated localization.
- Dimerization of Ret/ptc2 facilitates the assembly of localized signaling complexes involving Enigma and Shc.
- These findings elucidate key molecular events in Ret/ptc2-driven oncogenesis.