Linked Life Data

17452978

Source:http://linkedlifedata.com/resource/pubmed/id/17452978

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
44
pubmed:dateCreated
2007-9-27
pubmed:abstractText
Most gastrointestinal stromal tumors (GISTs) express oncogenic and constitutively active forms of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase proteins, and these kinase oncoproteins serve as targets for effective therapies. Given that mutant KIT oncoproteins serve crucial transforming roles in GISTs, we evaluated interactions with the KIT oncoproteins and determined signaling pathways that are dependent on KIT oncogenic activation in GISTs. Tyrosine-phosphorylated KIT oncoproteins interacted with PDGFRA, PDGFRB, phosphatidylinositol 3-kinase (PI3-K) and PKCtheta in GIST cells, and these interactions were abolished by KIT inhibition with imatinib or PKC412 or KIT RNAi. Notably, tyrosine-phosphorylated PDGFRA was prominent in frozen GIST tumors expressing KIT oncoproteins, suggesting that KIT-mediated PDGFRA phosphorylation is an efficient and biologically consequential mechanism in GISTs. Activated signaling intermediates were identified by immunoaffinity purification of tyrosine-phosphorylated proteins in GIST cells before and after treatment with KIT inhibitors, and these analyses show that GRB2, SHC, CBL and MAPK activation are largely KIT dependent in GISTs, whereas PI3-K, STAT1 and STAT3 activation are partially KIT dependent. In addition, we found that phosphorylation of several tyrosine kinase proteins - including JAK1 and EPHA4 - did not depend on KIT activation. Likewise, paxillin activation was independent of the KIT oncogenic signal. These studies identify signaling pathways that can provide both KIT-dependent and KIT-independent therapeutic synergies in GIST, and thereby highlight clinical strategies that might consolidate GIST therapeutic response to KIT/PDGFRA inhibition.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0950-9232
pubmed:author
pubmed:issnType
Print
pubmed:day
27
pubmed:volume
26
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6386-95
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:17452978-Antineoplastic Agents, pubmed-meshheading:17452978-Blotting, Western, pubmed-meshheading:17452978-Drug Resistance, Neoplasm, pubmed-meshheading:17452978-Gastrointestinal Stromal Tumors, pubmed-meshheading:17452978-Humans, pubmed-meshheading:17452978-Immunoprecipitation, pubmed-meshheading:17452978-Mutation, pubmed-meshheading:17452978-Phosphatidylinositol 3-Kinases, pubmed-meshheading:17452978-Phosphorylation, pubmed-meshheading:17452978-Protein Kinase C-delta, pubmed-meshheading:17452978-Proto-Oncogene Proteins c-kit, pubmed-meshheading:17452978-RNA, Small Interfering, pubmed-meshheading:17452978-Receptor, Platelet-Derived Growth Factor alpha, pubmed-meshheading:17452978-Receptor, Platelet-Derived Growth Factor beta, pubmed-meshheading:17452978-STAT1 Transcription Factor, pubmed-meshheading:17452978-STAT3 Transcription Factor, pubmed-meshheading:17452978-Tumor Cells, Cultured, pubmed-meshheading:17452978-Tyrosine
pubmed:year
2007
pubmed:articleTitle
KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance.
pubmed:affiliation
Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115, USA. mzhu2@partners.org
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't