Home Blog of Signal Transduction Protein Tyrosine Kinase FAK Inhibition of focal adhesion turnover prevents osteoblastic differentiation through β-catenin mediated transduction of pro-osteogenic substrate

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Inhibition of focal adhesion turnover prevents osteoblastic differentiation through β-catenin mediated transduction of pro-osteogenic substrate

The mechanism by which substrate surface characteristics are transduced by osteoblastic cells and their progenitors is not fully known. Data from previous studies by our group suggest the involvement of β-catenin in the mechanism by which substrate surface characteristics are transduced. This focal adhesion and β-catenin mediated mechanism functions through the liberation of β-catenin from focal adhesion complexes in response to pro-osteogenic substrate (POS) characteristics. After liberation, β-catenin translocates and facilitates upregulation of genes associated with osteogenesis. It is not known whether the observed correlation between focal adhesion turnover and β-catenin translocation directly results from focal adhesion turnover. In this study we inhibited focal adhesion turnover using a focal adhesion kinase inhibitor PF-573228. We found that inhibition of focal adhesion turnover resulted in an abrogation of the more rapid translocation and increased transcriptional activity of β-catenin induced by POS. In addition, inhibition of focal adhesion turnover mitigated the increase in osteoblastic differentiation induced by a POS as measured by alkaline phosphatase enzymatic activity and osteogenic gene and protein expression. Together, these data, coupled with previous findings, suggest that the observed β-catenin translocation is a result of focal adhesion turnover, providing evidence for a focal adhesion initiated, β-catenin mediated mechanism of substrate surface signal transduction.

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S2013 PF-573228 PF-573228 is an ATP-competitive inhibitor of FAK with IC50 of 4 nM in a cell-free assay, ~50- to 250-fold selective for FAK than Pyk2, CDK1/7 and GSK-3β. PF-573228 induces apoptosis.

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FAK