Tyrosine dephosphorylation of glycogen synthase kinase‐3 is involved in its extracellular signal‐dependent inactivation

Abstract

We examined whether extracellular signals regulate glycogen synthase kinase-3 (GSK-3) activity through tyrosine dephosphorylation of GSK-3. In resting Chinese hamster ovary cells overexpressing the human insulin receptor (CHO-IR cells), GSK-3 was tyrosine-phosphorylated and active. Insulin and 12-O-tetradecanoylphorbol 13-acetate (TPA) induced inactivation and tyrosine dephosphorylation of GSK-3. It is known that Ser-9 of GSK-313 is phosphorylated in response to insulin and that the phosphorylation of this amino acid residue causes inactivation of GSK-313. However, the ectopically expressed GSK-3I] a9, in which the N-terminal nine amino acids of GSK-313 were deleted, was still inactivated and tyrosine-dephosphorylated in response to insulin. Protein phosphatase 2A treatment partially reversed insulin-induced GSK-31~ inactivation, but did not change GSK-3~ A9 inactivation. In CHO-IR cells where protein kinase C was down-regulated, TPA neither inactivated nor tyrosine-dephosphorylated GSK-3. However, insulin inactivated and tyrosinedephosphorylated GSK-3, although to a lesser degree than in the control cells. These results suggest that in addition to serine phosphorylation, tyrosine dephosphorylation of GSK-3 is also important for the regulation of GSK-3 activity in response to extracellular signals and that insulin regulates GSK-3 activity through both protein kinase C-dependent as well as protein kiuase C-independent pathways.

The uncovering of a novel regulatory mechanism for PLD2: Formation of a ternary complex with protein tyrosine phosphatase PTP1B and growth factor receptor-bound protein GRB2

“…Presumably, this kinase could in turn activate the PTP1b in a signaling complex. There are many examples where a protein tyrosine phosphatase regulates kinase function [37][38][39][40][41][42][43][44][45][46].…”

Convergence of Multiple Signaling Cascades at Glycogen Synthase Kinase 3: Edg Receptor-Mediated Phosphorylation and Inactivation by Lysophosphatidic Acid through a Protein Kinase C-Dependent Intracellular Pathway

“…However, a recent study indicates that Wnt causes GSK-3␤ inhibition independently of serine-9 phosphorylation (16). There are other regulatory mechanisms, such as phosphorylation of tyrosine residues, for the control of GSK-3␤ activity (47,64). Wnt signaling couples to the cytosolic and nuclear accumulation of ␤-catenin and the subsequent transactivation of ␤-catenin target genes associated with GSK-3␤ inhibition (6).…”

Phosphorylation of β-Catenin by Cyclic AMP-Dependent Protein Kinase Stabilizes β-Catenin through Inhibition of Its Ubiquitination

“…pGEX-2T/GSK-3␤, pMAL-c2/rAxin, pGEX-2T/␤-catenin, pRSETA/␤-catenin, pCGN/␤-catenin, pBJ-Myc/rAxin, pBacPAK9/MycFbw1, pBacPAK8/HA-Cul1, pBacPAK8/His 6 -T7-Skp1, pBacPAK8/Myc-Rbx1, pET23B/Myc-Uba1-His 6 , pRSETB/hUbc5a-FLAG, pEF-BOS-HA/hTcf-4E, and pEF-BOS-HA/hTcf-4E-(⌬1-53) were constructed as described previously (13,14,19,21,22,32,40). pMAL-c2/hCKI␣, pCGN/␤-catenin SA , pCGN/␤-catenin T510A , pCGN/␤-catenin S675A , pRSETA/␤-catenin T510A , pRSETA/␤-catenin S675A , and pCGN/PKAc were made by inserting the respective cDNA fragments generated by PCR into the vector.…”