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Title:
Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade | Journal of Biology
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Background The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as a
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Keywords {🔍}
lkb, ampkk, ampk, protein, cells, kinase, article, activity, pubmed, stradα, figure, activation, google, scholar, domain, catalytic, cas, moα, ampkα, phosphorylation, complexes, kinases, hela, cell, thr, complex, antibody, results, recombinant, expressed, antibodies, activate, amp, previously, wildtype, expression, upstream, ampactivated, activated, gstampkα, antilkb, lanes, purified, buffer, phenformin, substrate, control, hardie, aica, riboside,
Topics {✒️}
5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside protein kinase complement gst-tagged wild-type lkb1 stably expressing wild-type gst-tagged kinase-inactive mutant full length gst-ampkα1 full-length gst-ampkα1 ste20-related pseudokinase stradα/β open access license insulin signal transduction castrate-resistant prostate cancer amp-activated protein kinase anti-diabetic drugs rosiglitazone serine/threonine protein kinase hela cell-extract protein retroviral gag-pol genes cold spring harbor article download pdf camp-dependent protein kinase gst-ampkα1 catalytic domain gst-ampkα1-catalytic domain pre-immune control immunoglobulin prepacked q-sepharose columns familial peutz-jeghers syndrome peutz-jeghers syndrome locus calmodulin-dependent protein kinase coomassie-blue-stained gels cyclin-dependent kinase inhibitor anti-ampkα1 catalytic domain wild-type lkb1 correlated infra-red laser scanner peutz-jeghers cancer syndrome plasmids encoding myc-ampkα1 untransfected hek-293t cells gst-α1 catalytic domain protein kinase cascade full size image adenine nucleotide-independent mechanism expressed wild-type lkb1 lkb1-null cell line kinase-inactive mutant lkb1 protein g-sepharose beads 4–12% bis-tris gels kinase-dead lkb1 mutant phosphospecific anti-pt172 antibody wild-type fibroblasts lkb1-knockout mouse embryos sheep anti-human lkb1 drug 5-aminoimidazole-4-carboxamide international cancer research
Questions {❓}
- Corton JM, Gillespie JG, Hawley SA, Hardie DG: 5-Aminoimidazole-4-carboxamide ribonucleoside: a specific method for activating AMP-activated protein kinase in intact cells?
- The identity of the polypeptide labeled '?
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headline:Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade
description:The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as a 'metabolic master switch' and inhibits cell proliferation. Activation requires phosphorylation of Thr172 of AMPK within the activation loop by upstream kinases (AMPKKs) that have not been identified. Recently, we identified three related protein kinases acting upstream of the yeast homolog of AMPK. Although they do not have obvious mammalian homologs, they are related to LKB1, a tumor suppressor that is mutated in the human Peutz-Jeghers cancer syndrome. We recently showed that LKB1 exists as a complex with two accessory subunits, STRADα/β and MO25α/β. We report the following observations. First, two AMPKK activities purified from rat liver contain LKB1, STRADα and MO25α, and can be immunoprecipitated using anti-LKB1 antibodies. Second, both endogenous and recombinant complexes of LKB1, STRADα/β and MO25α/β activate AMPK via phosphorylation of Thr172. Third, catalytically active LKB1, STRADα or STRADβ and MO25α or MO25β are required for full activity. Fourth, the AMPK-activating drugs AICA riboside and phenformin do not activate AMPK in HeLa cells (which lack LKB1), but activation can be restored by stably expressing wild-type, but not catalytically inactive, LKB1. Fifth, AICA riboside and phenformin fail to activate AMPK in immortalized fibroblasts from LKB1-knockout mouse embryos. These results provide the first description of a physiological substrate for the LKB1 tumor suppressor and suggest that it functions as an upstream regulator of AMPK. Our findings indicate that the tumors in Peutz-Jeghers syndrome could result from deficient activation of AMPK as a consequence of LKB1 inactivation.
datePublished:2003-09-24T00:00:00Z
dateModified:2003-09-24T00:00:00Z
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HeLa Cell
Additional Data File
Phenformin
Upstream Kinase
Phosphospecific Antibody
Life Sciences
general
Biomedicine
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headline:Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade
description:The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as a 'metabolic master switch' and inhibits cell proliferation. Activation requires phosphorylation of Thr172 of AMPK within the activation loop by upstream kinases (AMPKKs) that have not been identified. Recently, we identified three related protein kinases acting upstream of the yeast homolog of AMPK. Although they do not have obvious mammalian homologs, they are related to LKB1, a tumor suppressor that is mutated in the human Peutz-Jeghers cancer syndrome. We recently showed that LKB1 exists as a complex with two accessory subunits, STRADα/β and MO25α/β. We report the following observations. First, two AMPKK activities purified from rat liver contain LKB1, STRADα and MO25α, and can be immunoprecipitated using anti-LKB1 antibodies. Second, both endogenous and recombinant complexes of LKB1, STRADα/β and MO25α/β activate AMPK via phosphorylation of Thr172. Third, catalytically active LKB1, STRADα or STRADβ and MO25α or MO25β are required for full activity. Fourth, the AMPK-activating drugs AICA riboside and phenformin do not activate AMPK in HeLa cells (which lack LKB1), but activation can be restored by stably expressing wild-type, but not catalytically inactive, LKB1. Fifth, AICA riboside and phenformin fail to activate AMPK in immortalized fibroblasts from LKB1-knockout mouse embryos. These results provide the first description of a physiological substrate for the LKB1 tumor suppressor and suggest that it functions as an upstream regulator of AMPK. Our findings indicate that the tumors in Peutz-Jeghers syndrome could result from deficient activation of AMPK as a consequence of LKB1 inactivation.
datePublished:2003-09-24T00:00:00Z
dateModified:2003-09-24T00:00:00Z
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HeLa Cell
Additional Data File
Phenformin
Upstream Kinase
Phosphospecific Antibody
Life Sciences
general
Biomedicine
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