RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase.
Constitutive activation of the RET proto-oncogene in papillary thyroid carcinomas results from rearrangements linking the promoter(s) and N-terminal domains of unrelated genes to the C-terminus of RET tyrosine kinase (RET/PTC). RET/PTC expression has been demonstrated to inhibit transcription of thyroid-specific genes. To study the signal transduction pathways responsible for this, we generated PCCL3 thyroid cells with doxycycline-inducible expression of RET/PTC3, RET/PTC3(Y541F), or PTC2/PDZ. Acute expression of RET/PTC(Y541F) appropriately interacted with Shc, an intermediate in the activation of the Ras pathway, but failed to activate PLCgamma. By contrast, PTC2/PDZ failed to bind Shc, but interacted normally with PLCgamma. Acute expression of RET/PTC3 or RET/PTC3(Y541F), but not PTC2/PDZ, inhibited TSH-induced Tg and NIS expression, suggesting that activation of Shc-Ras, but not PLCgamma, is required for RET/PTC-induced dedifferentiation. Accordingly, acute expression of H-Ras(V12) or of a constitutively active MEK1 also blocked TSH-induced expression of Tg and NIS. Moreover, MEK inhibitors restored Tg and NIS levels. In conclusion, activation of the Ras/Raf/MEK/MAPK pathway through Shc mediates RET/PTC-induced thyroid cell dedifferentiation. This suggests that inhibition of this pathway may promote redifferentiation in poorly differentiated thyroid carcinomas with constitutive activation of either Ras or RET/PTC.
Knauf
Jeffrey A
JA
Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Jeffrey.Knauf@UC.EDU
Kuroda
Hiroaki
H
Basu
Saswata
S
Fagin
James A
JA
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002454:Cell Differentiation; D011905:Genes, ras / Q000502:physiology*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D051381:Rats; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013964:Thyroid Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C000715470:MAS1 protein, human; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D000090063:Proto-Oncogene Mas; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases