RET signals through focal adhesion kinase in medullary thyroid cancer cells.
BACKGROUND
The RET proto-oncogene is implicated in medullary thyroid cancer (MTC) and has been shown to signal indirectly to focal adhesion kinase (FAK) in cell types other than MTC. We have previously shown that FAK is phosphorylated in MTC cells. We hypothesized that inhibition of RET with pharmacologic inhibitors or by depletion with siRNA would decrease FAK phosphorylation in MTC cells, thereby implicating a RET-FAK signaling pathway.


METHODS
Human MTC cells (TT cells) were treated with pharmacologic inhibitors or transfected with RET siRNA. Total protein was detected by immunoblotting. Phosphorylated FAK was detected by immunoprecipitating total FAK and immunoblotting with antiphosphotyrosine.


RESULTS
Treatment of MTC cells with the inhibitor PP2 significantly inhibited RET phosphorylation and, to a lesser extent, FAK phosphorylation. Imatinib mesylate inhibited FAK phosphorylation only at high doses. RET siRNA significantly decreased RET expression and FAK phosphorylation.


CONCLUSIONS
RET signals through FAK in MTC cells. Whether this is due to a direct or indirect interaction is not yet clear. PP2 or a similar inhibitor might be a useful treatment for MTC.
Panta
Ganesh R
GR
Surgical Service 112, Central Arkansas Veterans Healthcare System, 4300 W. 7th Street, Little Rock, AR 72205, USA.
Nwariaku
Fiemu
F
Kim
Lawrence T
LT
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000503:physiopathology*; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000503:physiopathology*
D000970:Antineoplastic Agents; D001549:Benzamides; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human