Linked Life Data

15574420

Source:http://linkedlifedata.com/resource/pubmed/id/15574420

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2005-2-14
pubmed:abstractText
SHP2 was recently found to down-regulate PI3K activation by dephosphorylating Gab1 but the mechanisms explaining the positive role of the Gab1/SHP2 pathway in EGF-induced Ras activation remain ill defined. Substrate trapping experiments now suggest that SHP2 dephosphorylates other Gab1 phosphotyrosines located within a central region displaying four YXXP motifs. Because these sites are potential docking motifs for Ras-GAP, we tested whether SHP2 dephosphorylates them to facilitate Ras activation. We observed that a Gab1 construct preventing SHP2 recruitment promoted membrane relocation of RasGAP. Moreover, a RasGAP-inactive mutant restored the activation of Ras in cells transfected with SHP2-inactivating Gab1 mutant or in SHP2-deficient fibroblasts, supporting the hypothesis that RasGAP is a downstream target of SHP2. To determine whether Gab1 is a RasGAP-binding partner, a Gab1 mutant deleted of four YXXP motifs was produced. The deletion suppressed RasGAP redistribution and restored the defective Ras activation caused by SHP2-inactivating mutations. Moreover, Gab1 was found to interact with RasGAP SH2 domains, only under conditions where SHP2 is not activated. To identify Ras-GAP-binding sites, Tyr to Phe mutants of Gab1 YXXP motifs were produced. Gab1 constructs mutated on Tyr(317) were severely affected in RasGAP binding and were the most active in compensating for Ras-defective activation and blocking RasGAP redistribution induced by SHP2 inactivation. We have thus localized on Gab1 a Ras-negative regulatory tyrosine phosphorylation site involved in RasGAP binding and showed that an important SHP2 function is to down-regulate its phosphorylation to disengage RasGAP and sustain Ras activation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
18
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5350-60
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:15574420-Amino Acid Sequence, pubmed-meshheading:15574420-Animals, pubmed-meshheading:15574420-Binding Sites, pubmed-meshheading:15574420-Cell Line, pubmed-meshheading:15574420-Cercopithecus aethiops, pubmed-meshheading:15574420-Enzyme Activation, pubmed-meshheading:15574420-Epidermal Growth Factor, pubmed-meshheading:15574420-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:15574420-Mice, pubmed-meshheading:15574420-Models, Biological, pubmed-meshheading:15574420-Mutation, pubmed-meshheading:15574420-Phosphatidylinositol 3-Kinases, pubmed-meshheading:15574420-Phosphoproteins, pubmed-meshheading:15574420-Phosphorylation, pubmed-meshheading:15574420-Protein Binding, pubmed-meshheading:15574420-Protein Tyrosine Phosphatase, Non-Receptor Type 11, pubmed-meshheading:15574420-Protein Tyrosine Phosphatases, pubmed-meshheading:15574420-Vero Cells, pubmed-meshheading:15574420-ras GTPase-Activating Proteins, pubmed-meshheading:15574420-ras Proteins
pubmed:year
2005
pubmed:articleTitle
A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation.
pubmed:affiliation
Département Lipoprotéines et Médiateurs Lipidiques, INSERM U563, Hôpital Purpan, 31300 Toulouse, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't