GSK-3 and β-catenin
Your Editors' Choice on the effect of N-CAM on β-catenin failed to note that the phosphorylation state of GSK-3 (either or β) has no effect on β-catenin levels in cells. Phosphorylation of Serine 9 (GSK-3β) or Serine 21 (GSK-3; both kinases are equivalent in their capacity to regulate β-catenin) is irrelevant to β-catenin phosphorylation. Moreover, potent agonists of Serine 9/21 phosphorylation have little, if any, effect on β-catenin levels. N-CAM may well be modulating β-catenin levels by some mechanism, but it is very unlikely to be achieving this via serine phosphorylation of GSK-3 since it is only the 5% or so of cellular GSK-3 associated with Axin that is relevant to β-catenin regulation. Indeed, genetic reduction of total GSK-3 levels to just 25% of normal (far higher levels of inhibition than can be achieved through serine phosphorylation) leaves β-catenin regulation intact.
There is a plethora of papers that correlate serine phosphorylation of GSK-3 with stabilization of β-catenin. However, correlation does not make for a direct connection and there are compelling genetic data to suggest no connection between these phenomena.
James R. Woodgett Samuel Lunenfeld Research Institute
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882