Linked Life Data

19535334

Source:http://linkedlifedata.com/resource/pubmed/id/19535334

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
39
pubmed:dateCreated
2009-9-21
pubmed:abstractText
ITK-SYK, a novel fusion tyrosine kinase (FTK) resulting from a recurrent t(5;9)(q33;q22), was recently identified in a poorly understood subset of peripheral T-cell lymphomas. However, the biochemical and functional properties of ITK-SYK are unknown. Here we demonstrate that ITK-SYK is a catalytically active tyrosine kinase that is sensitive to an established inhibitor of SYK. The expression of ITK-SYK, but not SYK, transformed NIH3T3 cells, inducing loss of contact inhibition and formation of anchorage-independent colonies in soft agar, in a kinase activity-dependent manner. ITK-SYK is unusual among FTKs in having an N-terminal phosphatidylinositol 3,4,5-trisphosphate-binding pleckstrin homology (PH) domain. Introduction of a well characterized loss-of-function mutation (R29C) into the PH domain of ITK-SYK inhibited its phosphorylation, markedly reduced its catalytic activity, and abrogated its ability to activate the ERK signaling pathway and to transform NIH3T3 cells. Although ITK-SYK was membrane-associated, ITK-SYK-R29C was not. However, each of these properties could be recovered by retargeting ITK-SYK-R29C back to the plasma membrane by the addition of an N-terminal myristylation sequence. Consistent with a model in which ITK-SYK requires PH domain-mediated binding to phosphatidylinositol 3,4,5-trisphosphate generated by phosphatidylinositol 3-kinase (PI3K), ITK-SYK activity was reduced by pharmacological inhibition of PI3K and increased by co-expression with a constitutively active form of PI3K. Together, these findings identify ITK-SYK as an active, transforming FTK dependent upon PH domain-mediated membrane localization, identify a novel mechanism for activation of an oncogenic FTK, and suggest ITK-SYK as a rational therapeutic target for t(5;9)(q33;q22)-positive lymphomas.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
25
pubmed:volume
284
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
26871-81
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed-meshheading:19535334-Animals, pubmed-meshheading:19535334-Binding Sites, pubmed-meshheading:19535334-Blotting, Western, pubmed-meshheading:19535334-Cell Line, pubmed-meshheading:19535334-Cell Membrane, pubmed-meshheading:19535334-Cell Transformation, Neoplastic, pubmed-meshheading:19535334-Humans, pubmed-meshheading:19535334-Immunoprecipitation, pubmed-meshheading:19535334-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:19535334-Jurkat Cells, pubmed-meshheading:19535334-Lymphoma, T-Cell, Peripheral, pubmed-meshheading:19535334-Mice, pubmed-meshheading:19535334-Microscopy, Confocal, pubmed-meshheading:19535334-Mutation, Missense, pubmed-meshheading:19535334-NIH 3T3 Cells, pubmed-meshheading:19535334-Oncogene Proteins, Fusion, pubmed-meshheading:19535334-Phosphatidylinositol 3-Kinases, pubmed-meshheading:19535334-Phosphatidylinositol Phosphates, pubmed-meshheading:19535334-Protein-Tyrosine Kinases, pubmed-meshheading:19535334-Signal Transduction, pubmed-meshheading:19535334-Transfection
pubmed:year
2009
pubmed:articleTitle
The lymphoma-associated fusion tyrosine kinase ITK-SYK requires pleckstrin homology domain-mediated membrane localization for activation and cellular transformation.
pubmed:affiliation
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't