Linked Life Data

17255109

Source:http://linkedlifedata.com/resource/pubmed/id/17255109

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2007-3-19
pubmed:abstractText
In the context of fibroblast growth factor (FGF) signaling, Sprouty2 (Spry2) is the most profound inhibitor of the Ras/ERK pathway as compared with other Spry isoforms. An exclusive, necessary, but cryptic PXXPXR motif in the C terminus of Spry2 is revealed upon stimulation. The activation of Spry2 appears to be linked to sequences in the N-terminal half of the protein and correlated with a bandshifting seen on SDS-PAGE. The band-shifting is likely caused by changes in the phosphorylation status of key Ser and Thr residues following receptor stimulation. Dephosphorylation of at least two conserved Ser residues (Ser-112 and Ser-115) within a conserved Ser/Thr sequence is accomplished upon stimulation by a phosphatase that binds to Spry2 around residues 50-60. We show that human Spry2 co-immunoprecipitates with both the catalytic and the regulatory subunits of protein phosphatase 2A (PP2A-C and PP2A-A, respectively) in cells upon FGF receptor (FGFR) activation. PP2A-A binds directly to Spry2, but not to Spry2Delta50-60 (Delta50-60), and the activity of PP2A increases with both FGF treatment and FGFR1 overexpression. c-Cbl and PP2A-A compete for binding centered around Tyr-55 on Spry2. We show that there are at least two distinct pools of Spry2, one that binds PP2A and another that binds c-Cbl. c-Cbl binding likely targets Spry2 for ubiquitin-linked destruction, whereas the phosphatase binding and activity are necessary to dephosphorylate specific Ser/Thr residues. The resulting change in tertiary structure enables the Pro-rich motif to be revealed with subsequent binding of Grb2, a necessary step for Spry2 to act as a Ras/ERK pathway inhibitor in FGF signaling.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
282
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9117-26
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:17255109-Amino Acid Sequence, pubmed-meshheading:17255109-Animals, pubmed-meshheading:17255109-Extracellular Signal-Regulated MAP Kinases, pubmed-meshheading:17255109-Humans, pubmed-meshheading:17255109-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:17255109-Molecular Sequence Data, pubmed-meshheading:17255109-PC12 Cells, pubmed-meshheading:17255109-Phosphoprotein Phosphatases, pubmed-meshheading:17255109-Phosphorylation, pubmed-meshheading:17255109-Protein Binding, pubmed-meshheading:17255109-Protein Phosphatase 2, pubmed-meshheading:17255109-Proto-Oncogene Proteins c-cbl, pubmed-meshheading:17255109-Rats, pubmed-meshheading:17255109-Receptors, Fibroblast Growth Factor, pubmed-meshheading:17255109-Sequence Homology, Amino Acid, pubmed-meshheading:17255109-Signal Transduction
pubmed:year
2007
pubmed:articleTitle
Direct binding of PP2A to Sprouty2 and phosphorylation changes are a prerequisite for ERK inhibition downstream of fibroblast growth factor receptor stimulation.
pubmed:affiliation
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't