The Regulation of GSK3 Activity by Insulin and Growth Factors

GSK3 can be inhibited via the phosphorylation of a serine residue near the N terminus of the protein (Ser21 in GSK3a, Ser9 in GSK3P) [22]. This serine lies in an Arg-Xaa-Arg-Xaa-Xaa-Ser sequence, which is a consensus motif for phosphorylation by several protein kinases that are components of different signal transduction pathways (Fig. 1). Protein kinase B (PKB, also called Akt) inhibits GSK3 in response to signals that activate class I phos-phatidylinositol (PtdIns) 3-kinases and elevate the level of PtdIns(3,4,5)P3 [22]; MAPK-activated protein kinase 1 (MAPKAP-K1, also called RSK) inhibits GSK3 following stimulation by signals that activate the classical MAPK cascade [23, 24]; and S6K1 inhibits GSK3 in response to amino acids acting via the protein kinase mTOR [25].

In embryonic stem cells that do not express 3-phospho-inositide-dependent protein kinase 1 (PDK1), an essential upstream activator of both PKB and MAPKAP-K1, the PKB-mediated inhibition of GSK3 (induced by insulin-like growth factor 1) and the MAPKAP-K1-mediated inhibition of GSK3 (induced by the tumor-promoting phorbol ester TPA) do not occur [26]. This genetic evidence supports the view that GSK3 can be inhibited by PKB and MAPKAP-K1 in vivo.

The mechanism by which phosphorylation inhibits GSK3 has been elucidated. The phosphorylated N terminus becomes a pseudosubstrate occupying the same binding pocket as the priming phosphate of substrates [14,16]. This suggests that

Figure 1 GSK3 can be inhibited by several different agonists. The inhibition of GSK3 by growth factors, amino acids, and hormones, such as insulin, occurs by a different mechanism than does inhibition of GSK3 by Wnts. Protein kinases that are activated by these agonists, such as PKB, MAP-KAP-K1, and S6 kinase (S6K), phosphorylate the N terminus of GSK3 on a serine residue (Ser9 of GSK3P and Ser21 of GSK3a). In contrast, Wnt signaling does not lead to an increase in Ser9/Ser21 phosphorylation and instead may involve the displacement of Axin and P-catenin from GSK3 via the binding of FRAT and Dishevelled to GSK3.

Figure 1 GSK3 can be inhibited by several different agonists. The inhibition of GSK3 by growth factors, amino acids, and hormones, such as insulin, occurs by a different mechanism than does inhibition of GSK3 by Wnts. Protein kinases that are activated by these agonists, such as PKB, MAP-KAP-K1, and S6 kinase (S6K), phosphorylate the N terminus of GSK3 on a serine residue (Ser9 of GSK3P and Ser21 of GSK3a). In contrast, Wnt signaling does not lead to an increase in Ser9/Ser21 phosphorylation and instead may involve the displacement of Axin and P-catenin from GSK3 via the binding of FRAT and Dishevelled to GSK3.

the extent to which phosphorylation inhibits GSK3 activity in vivo may vary between substrates and will depend on the affinity of any particular substrate for GSK3.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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