Publication Date:
2008-07-03
Description:
On activation by receptors, the ubiquitously expressed class IA isoforms (p110alpha and p110beta) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades. Recent studies have demonstrated specific functions for p110alpha in growth factor and insulin signalling. To probe for distinct functions of p110beta, we constructed conditional knockout mice. Here we show that ablation of p110beta in the livers of the resulting mice leads to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt, suggesting the involvement of a kinase-independent role of p110beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110beta also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110beta-null cells with a wild-type or kinase-dead allele of p110beta demonstrated that p110beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110beta was required for G-protein-coupled receptor signalling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumour formation induced by Pten loss, ablation of p110beta (also known as Pik3cb), but not that of p110alpha (also known as Pik3ca), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110beta, and strongly indicate the kinase-dependent functions of p110beta as a promising target in cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750091/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750091/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jia, Shidong -- Liu, Zhenning -- Zhang, Sen -- Liu, Pixu -- Zhang, Lei -- Lee, Sang Hyun -- Zhang, Jing -- Signoretti, Sabina -- Loda, Massimo -- Roberts, Thomas M -- Zhao, Jean J -- P01 CA050661/CA/NCI NIH HHS/ -- P01 CA050661-200001/CA/NCI NIH HHS/ -- P01 CA089021/CA/NCI NIH HHS/ -- P01 CA089021-06A1/CA/NCI NIH HHS/ -- P50 CA089393/CA/NCI NIH HHS/ -- P50 CA089393-08S1/CA/NCI NIH HHS/ -- P50 CA090381/CA/NCI NIH HHS/ -- P50 CA090381-05/CA/NCI NIH HHS/ -- R01 CA030002/CA/NCI NIH HHS/ -- R01 CA030002-27/CA/NCI NIH HHS/ -- R01 CA134502/CA/NCI NIH HHS/ -- R01 CA134502-01/CA/NCI NIH HHS/ -- England -- Nature. 2008 Aug 7;454(7205):776-9. doi: 10.1038/nature07091. Epub 2008 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594509" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Cell Proliferation/drug effects
;
*Cell Transformation, Neoplastic
;
Epidermal Growth Factor/pharmacology
;
Fibroblasts/cytology
;
Glucose/*metabolism
;
Glucose Intolerance/enzymology/genetics
;
Homeostasis
;
Humans
;
Insulin/*metabolism/pharmacology
;
Insulin Resistance/genetics
;
Liver/enzymology/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
PTEN Phosphohydrolase/deficiency/genetics
;
Phosphatidylinositol 3-Kinases/deficiency/genetics/*metabolism
;
Phosphorylation/drug effects
;
Prostatic Neoplasms/enzymology/genetics/pathology
;
Proto-Oncogene Proteins c-akt/metabolism
;
Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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