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doi: 10.1242/10.1242/jcs.00384

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GSK-3: tricks of the trade for a multi-tasking kinase

Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada

View larger version (7K): [in a new window]   Fig. 1. Schematic representation of mammalian GSK-3 and GSK-3ß. Sites of serine and tyrosine phosphorylation are indicated with blue arrowheads. The glycine-rich N-terminal domain unique to GSK-3 and the conserved kinase domain shared by both isoforms are highlighted.

View larger version (39K): [in a new window]   Fig. 2. (A) Regulation of GSK-3ß activity by serine phosphorylation. In the resting cell, GSK-3ß is constitutively active. Both unprimed substrates and substrates phosphorylated by a priming kinase (PK) are capable of being phosphorylated by the active GSK-3ß. The priming phospho-residue at position N + 4, binds a pocket of positive charge arising from the arginine (R) and lysine (K) residues indicated. This directs a serine or threonine at position N to the active catalytic site (C.S.). When an inactivating kinase (IK) such as PKB/Akt phosphorylates GSK-3ß on serine 9 (S9), the phosphorylated N-terminus becomes a primed pseudo-substrate that occupies the positive binding pocket and active site of the enzyme, acting as a competitive inhibitor for true substrates. This prevents phosphorylation of any substrates. (B) Effect of mutating arginine 96 to alanine (R96A) on GSK-3ß activity. Since arginine 96 is a crucial component of the positive pocket that binds primed substrates, its mutation to an uncharged alanine residue disrupts the pocket so that primed substrates can no longer bind. The enzyme retains activity. Also, the S9-phosphorylated pseudosubstrate is no longer capable of inactivating the enzyme. As a consequence, GSK-3ß, whether S9-phosphorylated or not, can phosphorylate unprimed substrates, but not primed substrates. Note that unprimed and primed substrates interact with GSK-3 through different interfaces.

View larger version (48K): [in a new window]   Fig. 3. Central role of GSK-3 in the Wnt/ß-catenin pathway. In unstimulated cells, CKI phosphorylates ß-catenin on S45, priming it for subsequent phosphorylation by GSK-3 (S41, S37, S33), which targets ß-catenin for ubiquitylation and proteasomal degradation. The ankyrin repeat protein, Diversin (Div), may help recruit CKI to the destruction complex. Wnt stimulation activates the receptor Frizzled, which then signals through Dishevelled (Dvl), using an unclear mechanism, to inactivate ß-catenin phosphorylation. Unphosphorylated ß-catenin accumulates and then translocates to the nucleus where it transactivates genes regulated by TCF/LEF transcription factors. The GSK-3-binding protein (GBP/FRAT) may be involved in transmission of a Wnt signal by regulating binding of GSK-3 to the scaffold protein, axin.

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