Back to Search
Start Over
Constitutive diffuse activation of phosphoinositide 3-kinase at the plasma membrane by v-Src suppresses the chemotactic response to PDGF by abrogating the polarity of PDGF receptor signalling
- Source :
- Experimental Cell Research. 313:1090-1105
- Publication Year :
- 2007
- Publisher :
- Elsevier BV, 2007.
-
Abstract
- Cancer cells depend on chemotaxis for invasion and frequently overexpress and/or activate Src. We previously reported that v-Src accelerates motility by promoting phosphoinositide 3-kinase (PI3-K) signalling but abrogates chemotaxis. We here addressed the mechanism of the loss of chemotactic response to platelet-derived growth factor (PDGF) gradients in fibroblasts harbouring a thermosensitive v-Src kinase. At non-permissive temperature, PDGF receptor (PDGFR) signalling, assessed by phosphoY(751)-specific antibodies (a docking site for PI3-K), was not detected without PDGF and showed a concentration-dependent PDGF response. Both immunolabeling of PI3-K (p110) and live cell imaging of its product (phosphatidylinositol 3,4,5 tris-phosphate) showed PI3-K recruitment and activation at lamellipodia polarized towards a PDGF gradient. Centrosomes and PDGFR- and Src-bearing endosomes were also oriented towards this gradient. Upon v-Src thermoactivation, (i) Y(751) phosphorylation was moderately induced without PDGF and synergistically increased with PDGF; (ii) PI3-K was recruited and activated all along the plasma membrane without PDGF and did not polarize in response to a PDGF gradient; and (iii) polarization of centrosomes and of PDGFR-bearing endosomes were also abrogated. Thus, PDGF can further increase PDGFR auto-phosphorylation despite strong Src kinase activity, but diffuse downstream activation of PI3-K by Src abrogates cell polarization and chemotaxis: "signalling requires silence".
- Subjects :
- Cytoplasm
Platelet-derived growth factor
Endosome
Cell Line
Oncogene Protein pp60(v-src)
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Animals
Receptors, Platelet-Derived Growth Factor
Cytoskeleton
Centrosome
Platelet-Derived Growth Factor
Focal Adhesions
Phosphoinositide 3-kinase
biology
Kinase
Chemotaxis
Cell Membrane
Cell Biology
Fibroblasts
Rats
Cell biology
Enzyme Activation
chemistry
v-Src
biology.protein
Proto-Oncogene Proteins c-akt
Microtubule-Organizing Center
Platelet-derived growth factor receptor
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 00144827
- Volume :
- 313
- Database :
- OpenAIRE
- Journal :
- Experimental Cell Research
- Accession number :
- edsair.doi.dedup.....444b1d5e11951c0e671e11f1bb083fe7