scholarly journals Protein Kinase B/Akt Acts via Glycogen Synthase Kinase 3 To Regulate Recycling of αvβ3 and α5β1 Integrins

2004 ◽  
Vol 24 (4) ◽  
pp. 1505-1515 ◽  
Author(s):  
Marnie S. Roberts ◽  
Alison J. Woods ◽  
Trevor C. Dale ◽  
Peter van der Sluijs ◽  
Jim C. Norman
Keyword(s):  
Cell Migration ◽  
Protein Kinase ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Cell Spreading ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Promote Cell Migration ◽  
Integrin Ligands ◽  
Gsk 3Β

ABSTRACT Protein kinase B (PKB)/Akt is known to promote cell migration, and this may contribute to the enhanced invasiveness of malignant cells. To elucidate potential mechanisms by which PKB/Akt promotes the migration phenotype, we have investigated its role in the endosomal transport and recycling of integrins. Whereas the internalization of αvβ3 and α5β1 integrins and their transport to the recycling compartment were independent of PKB/Akt, the return of these integrins (but not internalized transferrin) to the plasma membrane was regulated by phosphatidylinositol 3-kinases and PKB/Akt. The blockade of integrin recycling and cell spreading on integrin ligands effected by inhibition of PKB/Akt was reversed by inhibition of glycogen synthase kinase 3 (GSK-3). Moreover, expression of nonphosphorylatable active GSK-3β mutant GSK-3β-A9 suppressed recycling of α5β1 and αvβ3 and reduced cell spreading on ligands for these integrins, indicating that PKB/Akt promotes integrin recycling by phosphorylating and inactivating GSK-3. We propose that the ability of PKB/Akt to act via GSK-3 to promote the recycling of matrix receptors represents a key mechanism whereby integrin function and cell migration can be regulated by growth factors.

scholarly journals Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1α and Mediates Its Destabilization in a VHL-Independent Manner

2007 ◽  
Vol 27 (9) ◽  
pp. 3253-3265 ◽  
Author(s):  
Daniela Flügel ◽  
Agnes Görlach ◽  
Carine Michiels ◽  
Thomas Kietzmann
Keyword(s):  
Protein Kinase ◽  
Metabolic Diseases ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Hypoxia Inducible Factor ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Independent Manner ◽  
Von Hippel Lindau ◽  
Gsk 3Β

ABSTRACT Hypoxia-inducible transcription factor 1α (HIF-1α) is a key player in the response to hypoxia. Additionally, HIF-1α responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1α is not a direct substrate for this kinase. Therefore, we investigated whether the protein kinase B target glycogen synthase kinase 3 (GSK-3) may have an impact on HIF-1α. We found that the inhibition or depletion of GSK-3 induced HIF-1α whereas the overexpression of GSK-3β reduced HIF-1α. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1α. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1α degradation in a VHL-independent manner. In line with these observations, the inhibition of the proteasome reversed the GSK-3 effects, indicating that GSK-3 may target HIF-1α to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1α stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.

Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B

Nature ◽  
1995 ◽  
Vol 378 (6559) ◽  
pp. 785-789 ◽  
Author(s):  
Darren A. E. Cross ◽  
Dario R. Alessi ◽  
Philip Cohen ◽  
Mirjana Andjelkovich ◽  
Brian A. Hemmings
Keyword(s):  
Protein Kinase ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals Essential Role for Protein Kinase B (PKB) in Insulin-induced Glycogen Synthase Kinase 3 Inactivation

1998 ◽  
Vol 273 (21) ◽  
pp. 13150-13156 ◽  
Author(s):  
Pascale C. van Weeren ◽  
Kim M. T. de Bruyn ◽  
Alida M. M. de Vries-Smits ◽  
Johan van Lint ◽  
Boudewijn M. Th. Burgering
Keyword(s):  
Protein Kinase ◽  
Essential Role ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase CβII in the diabetic fat tissue

2008 ◽  
Vol 294 (6) ◽  
pp. E1169-E1177 ◽  
Author(s):  
Ziva Liberman ◽  
Batya Plotkin ◽  
Tamar Tennenbaum ◽  
Hagit Eldar-Finkelman
Keyword(s):  
Protein Kinase ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Insulin Receptor Substrate ◽  
Fat Tissue ◽  
Insulin Receptor Substrate 1 ◽  
Gsk 3Β

Serine/threonine phosphorylation of insulin receptor substrate-1 (IRS-1) is an important negative modulator of insulin signaling. Previously, we showed that glycogen synthase kinase-3 (GSK-3) phosphorylates IRS-1 at Ser332. However, the fact that GSK-3 requires prephosphorylation of its substrates suggested that Ser336 on IRS-1 was the “priming” site phosphorylated by an as yet unknown protein kinase. Here, we sought to identify this “priming kinase” and to examine the phosphorylation of IRS-1 at Ser336 and Ser332 in physiologically relevant animal models. Of several stimulators, only the PKC activator phorbol ester PMA enhanced IRS-1 phosphorylation at Ser336. Treatment with selective PKC inhibitors prevented this PMA effect and suggested that a conventional PKC was the priming kinase. Overexpression of PKCα or PKCβII isoforms in cells enhanced IRS-1 phosphorylation at Ser336 and Ser332, and in vitro kinase assays verified that these two kinases directly phosphorylated IRS-1 at Ser336. The expression level and activation state of PKCβII, but not PKCα, were remarkably elevated in the fat tissues of diabetic ob/ob mice and in high-fat diet-fed mice compared with that from lean animals. Elevated levels of PKCβII were also associated with enhanced phosphorylation of IRS-1 at Ser336/332 and elevated activity of GSK-3β. Finally, adenoviral mediated expression of PKCβII in adipocytes enhancedphosphorylation of IRS-1 at Ser336. Taken together, our results suggest that IRS-1 is sequentially phosphorylated by PKCβII and GSK-3 at Ser336 and Ser332. Furthermore, these data provide evidence for the physiological relevance of these phosphorylation events in the pathogenesis of insulin resistance in fat tissue.

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