A New Strategy for Studying Protein Kinase B and Its Three Isoforms. Role of Protein Kinase B in Phosphorylating Glycogen Synthase Kinase-3, Tuberin, WNK1, and ATP Citrate Lyase†

Multifunctional ATP-citrate lyase kinase (ACLK) exhibits several properties that are similar to glycogen-synthase kinase-3 (GSK-3). The molecular cloning of two distinct mammalian GSK-3 cDNAs and a Drosophila melanogaster (fruitfly) homologue, zeste-white3sgg, has established the existence of a GSK-3 subfamily. A multifunctional protein kinase first identified as an ACLK has recently been shown to exhibit several similarities to the alpha- and beta-forms of GSK-3. Here we have used immunological and biochemical analyses to directly compare these enzymes. Thus purified preparations of ACLK isolated from brain and liver preferentially cross-react with anti-GSK-3 alpha antisera and phosphorylate previously defined substrates of GSK-3 at identical sites. Conversely, both alpha- and beta-forms of GSK-3 phosphorylated ATP-citrate lyase at the same site(s) targeted by ACLK. These, and other similarities, demonstrate ACLK to be identical with, or highly related to, GSK-3 alpha, the implications of which are discussed.

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Role of protein kinase B and the MAP kinase cascade in mediating the EGF-dependent inhibition of glycogen synthase kinase 3 in Swiss 3T3 cells1

FEBS Letters ◽

10.1016/s0014-5793(99)01434-9 ◽

1999 ◽

Vol 461 (1-2) ◽

pp. 120-124 ◽

Cited By ~ 62

Author(s):

Morag Shaw ◽

Philip Cohen

Keyword(s):

Protein Kinase ◽

Map Kinase ◽

Glycogen Synthase ◽

Protein Kinase B ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Map Kinase Cascade ◽

Dependent Inhibition ◽

Kinase Cascade

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Sequence of sites on ATP-citrate lyase and phosphatase inhibitor 2 phosphorylated by multifunctional protein kinase (a glycogen synthase kinase 3 like kinase)

Biochemistry ◽

10.1021/bi00485a011 ◽

1990 ◽

Vol 29 (33) ◽

pp. 7617-7624 ◽

Cited By ~ 45

Author(s):

Seethala Ramakrishna ◽

Guy D'Angelo ◽

William B. Benjamin

Keyword(s):

Protein Kinase ◽

Protein Kinase A ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Atp Citrate Lyase ◽

Multifunctional Protein ◽

Phosphatase Inhibitor ◽

Citrate Lyase ◽

Kinase A

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Activation of the protein kinase B and glycogen synthase kinase-3 signalling pathway during transient differentiation of human colon cancer HT-29 cells

Collection Symposium Series ◽

10.1135/css199903019 ◽

1999 ◽

Author(s):

Zdena Tuháčková ◽

Eva Šloncová ◽

Jan Hlaváček ◽

Vlasta Sovová ◽

Jiří Velek

Keyword(s):

Colon Cancer ◽

Protein Kinase ◽

Glycogen Synthase ◽

Protein Kinase B ◽

Human Colon ◽

Signalling Pathway ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Human Colon Cancer ◽

Ht 29

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

Molecular and Cellular Biology ◽

10.1128/mcb.00015-07 ◽

2007 ◽

Vol 27 (9) ◽

pp. 3253-3265 ◽

Cited By ~ 134

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.

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