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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
39
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pubmed:dateCreated |
2010-9-20
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pubmed:abstractText |
In organs involved in metabolic homeostasis, transmembrane ? and ?klothos direct FGFR signaling to control of metabolic pathways. Coordinate expression of ?klotho and FGFR4 is a property of mature hepatocytes. Genetic deletion of FGFR4 or ?klotho in mice disrupts hepatic cholesterol/bile acid and lipid metabolism. The deletion of FGFR4 has no effect on the proliferative response of hepatocytes after liver injury. However, its absence results in accelerated progression of dimethynitrosamine-initiated hepatocellular carcinomas, indicating that FGFR4 suppresses hepatoma proliferation. The mechanism underlying the FGFR4-mediated hepatoma suppression has not been addressed. Here we show that ?klotho expression is more consistently down-regulated in human and mouse hepatomas than FGFR4. Co-expression and activation by either endocrine FGF19 or cellular FGF1 of the FGFR4 kinase in a complex with ?klotho restricts cell population growth through induction of apoptotic cell death in both hepatic and nonhepatic cells. The ?klotho-FGFR4 partnership caused a depression of activated AKT and mammalian target of rapamycin while activating ERK1/2 that may underlie the pro-apoptotic effect. Our results show that ?klotho not only interacts with heparan sulfate-FGFR4 to form a complex with high affinity for endocrine FGF19 but also impacts the quality of downstream signaling and biological end points activated by either FGF19 or canonical FGF1. Thus the same ?klotho-heparan sulfate-FGFR4 partnership that mediates endocrine control of hepatic metabolism plays a role in cellular homeostasis and hepatoma suppression through negative control of cell population growth mediated by pro-apoptotic signaling.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/FGF19 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/FGFR4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Fgfr4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Fibroblast Growth Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Klb protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/MAPK1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/MTOR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Fibroblast Growth...,
http://linkedlifedata.com/resource/pubmed/chemical/TOR Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/fibroblast growth factor 15, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/mTOR protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1083-351X
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
24
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pubmed:volume |
285
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
30069-78
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pubmed:dateRevised |
2011-9-30
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pubmed:meshHeading |
pubmed-meshheading:20657013-Animals,
pubmed-meshheading:20657013-Apoptosis,
pubmed-meshheading:20657013-Carcinoma, Hepatocellular,
pubmed-meshheading:20657013-Cell Line, Tumor,
pubmed-meshheading:20657013-Cell Proliferation,
pubmed-meshheading:20657013-Fibroblast Growth Factors,
pubmed-meshheading:20657013-Humans,
pubmed-meshheading:20657013-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:20657013-MAP Kinase Signaling System,
pubmed-meshheading:20657013-Membrane Proteins,
pubmed-meshheading:20657013-Mice,
pubmed-meshheading:20657013-Mice, Knockout,
pubmed-meshheading:20657013-Mitogen-Activated Protein Kinase 1,
pubmed-meshheading:20657013-Mitogen-Activated Protein Kinase 3,
pubmed-meshheading:20657013-Protein-Serine-Threonine Kinases,
pubmed-meshheading:20657013-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:20657013-Receptor, Fibroblast Growth Factor, Type 4,
pubmed-meshheading:20657013-TOR Serine-Threonine Kinases
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pubmed:year |
2010
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pubmed:articleTitle |
Metabolic regulator betaKlotho interacts with fibroblast growth factor receptor 4 (FGFR4) to induce apoptosis and inhibit tumor cell proliferation.
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pubmed:affiliation |
IBT Proteomics and Nanotechnology Laboratory, Institute of Biosciences and Technology, Texas A & MHealth Science Center, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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