Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin.
The insulin-like growth factor (IGF) type 1 receptor is required for growth, transformation, and protection from apoptosis. IGFs can enhance cell migration, which is known to be influenced via regulation of the E-cadherin/beta-catenin complex. We sought to investigate whether IGF-1 modulated the interaction between E-cadherin and beta-catenin in human colorectal cancer cells. We used the C10 cell line, which we established and have previously shown to lack adenomatous polyposis coli, E-cadherin, or beta-catenin mutations. We found that IGF-1 stimulation enhanced tyrosine phosphorylation of two proteins, beta-catenin and insulin-receptor substrate 1, which formed a complex with E-cadherin. Tyrosine phosphorylation of beta-catenin was accompanied by rapid (<1 min) dissociation from E-cadherin at the plasma membrane, followed by relocation to the cellular cytoplasm. IGF-1 also enhanced the stability of beta-catenin protein. Despite this, we observed no enhancement of transcriptional activity in complex with T-cell factor 4 (Tcf-4) in human embryonic kidney 293 cells treated with IGF-1 or insulin alone. IGF-1 did, however, enhance transcriptional activity in combination with lithium chloride, an inhibitor of glycogen synthase kinase 3 beta, which also stabilizes beta-catenin. In conclusion, we have shown that IGF-1 causes tyrosine phosphorylation and stabilization of beta-catenin. These effects may contribute to transformation, cell migration, and a propensity for metastasis in vivo.
Playford
M P
MP
IGF Group, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom.
Bicknell
D
D
Bodmer
W F
WF
Macaulay
V M
VM
D002460:Cell Line; D015179:Colorectal Neoplasms / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology*; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017451:Receptors, Somatomedin; D015534:Trans-Activators; D051176:beta Catenin; D007334:Insulin-Like Growth Factor I