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Tumor promoter phorbol ester reversibly modulates tyrosine dephosphorylatioin/ inactivation of protein kinase FA/GSK‐3α in A431 cells

The signal transducrion mechanism of protein kinase FA/GSK‐3α by tyrosine phosphorylation in A431 cells was investigated. Kinase FA/GSK‐3α was found to exist in a highly tyrosine‐phosphorylated/activated state in resting cells but could be tyrosine‐dephosphorylated and inactivated to ∼60% of the control level when cells were acutely treated with 1 μM tumor phorbol ester (TPA) at 37oC for 30 min, as demonstrated by metabolic 32P‐labeling the cells, followed by immunoprecipitation and two‐dimensional phosphoamino acid analysis and by immunodetection in an antikinase FA/GSK‐3α immunoprecipitate kinase assay. Conversely, when cells were chronically treated with 1 μM TPA at 37°C for 24 h and processed under identical condetions, kinase FA/GSK‐3α was found to be rephosphorylated on tyrosine residue and reactivated to ∼130% of the original control level. Taken together, the results provide initial evidence that the phosphotyrosine content and cellular activity of kinase FA/GSK‐3α can be modulated in a reversible manner by short‐term and long‐term exposure of A431 cells to TPA. Since acute exposure of cells to TPA causes up‐regulation of cellular protein kinase C (PKC) activity and prolonged exposure to TPA causes down‐regulation of PKC, the results further suggest that the TPA‐mediated modulation of PKC may play a role in the regulation of tyrosine phosphorylation and concurrent activation of kinase FA/GSK‐3α in cells, representing a new mode of signal transduction pathway for the regulation of this multisubstrate/multifunctional protein kinase in cells.