Linked Life Data

18339867

Source:http://linkedlifedata.com/resource/pubmed/id/18339867

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2008-3-14
pubmed:abstractText
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is mutated or lost in 60% to 70% of advanced gliomas and is associated with malignant phenotypic changes such as migration, which contribute to the morbidity and mortality of this disease. Most of the tumor suppressor function of PTEN has been attributed to its ability to dephosphorylate the second messenger, phosphatidylinositol 3,4,5-triphosphate, resulting in the biological control of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Despite recent work suggesting that the protein phosphatase activity of PTEN controls glioma cell migration, the mechanisms by which this occurs are unclear. Herein, we show using glioma cell lines (U87MG and U373MG) stably transfected with wild-type PTEN or catalytically altered mutants of PTEN that PTEN controls integrin-directed migration in a lipid phosphatase, PI3K/AKT-independent manner. Confirming this observation, we show that the stable overexpression of COOH-terminal Src kinase, the physiologic negative regulator of SRC family kinases (SFK), or treatment with the SFK inhibitor PP1 abrogates glioma migration. The results provide direct evidence that the downstream effect of the protein phosphatase activity of PTEN is to suppress SFK and FYN, and to regulate RAC-GTPase activity after alpha(v) integrin stimulation. Furthermore, studying vitronectin-directed migration using (a) Fyn small interfering RNA and (b) astrocytes from Fyn heterozygous (+/-) mice, Pten heterozygous (+/-) mice, Pten and Fyn double heterozygous (+/-) mice, or Fyn knockout (-/-) mice confirmed a role of FYN in alpha(v) integrin-mediated haptotaxis in glial cells. Our combined results provide direct biochemical and genetic evidence that PTEN's protein phosphatase activity controls FYN kinase function in glioma cells and regulates migration in a PI3K/AKT-independent manner.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1538-7445
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
68
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1862-71
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:18339867-Animals, pubmed-meshheading:18339867-Astrocytes, pubmed-meshheading:18339867-Brain Neoplasms, pubmed-meshheading:18339867-Cell Line, Tumor, pubmed-meshheading:18339867-Cell Movement, pubmed-meshheading:18339867-Glioma, pubmed-meshheading:18339867-Humans, pubmed-meshheading:18339867-Integrin alphaVbeta3, pubmed-meshheading:18339867-Mice, pubmed-meshheading:18339867-Mice, Inbred C57BL, pubmed-meshheading:18339867-Mice, Knockout, pubmed-meshheading:18339867-Oncogene Protein v-akt, pubmed-meshheading:18339867-PTEN Phosphohydrolase, pubmed-meshheading:18339867-Phosphatidylinositol 3-Kinases, pubmed-meshheading:18339867-Proto-Oncogene Proteins c-fyn, pubmed-meshheading:18339867-Vitronectin, pubmed-meshheading:18339867-rac1 GTP-Binding Protein, pubmed-meshheading:18339867-src-Family Kinases
pubmed:year
2008
pubmed:articleTitle
The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration.
pubmed:affiliation
Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural