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001-es BibID:	BIBFORM061401
Első szerző:	Szöőr Árpád (orvos)
Cím:	Cell confluence induces switching from proliferation to migratory signaling by site-selective phosphorylation of PDGF receptors on lipid raft platforms / Árpád Szöőr, László Ujlaky-Nagy, Gábor Tóth, János Szöllősi, György Vereb
Dátum:	2016
ISSN:	0898-6568
Megjegyzések:	Platelet derived growth factor receptors (PDGFR) play an important role in tumor pathogenesis and are frequently overexpressed in glioblastoma. Earlier we have shown that only confluent glioblastoma cell cultures exhibit a biphasic calcium transient upon PDGF stimulation. Here, we examined how the change in cell density leads to differential cellular responses to the same PDGF stimulus. PDGF beta receptors and their specific phosphotyrosine residues were fluorescently colabeled on A172 and T98G glioblastoma cells. The distribution in cell membrane microdomains (lipid rafts) and the phosphorylation state of PDGFR was measured by confocal microscopy and quantitated by digital image processing. Corresponding bulk data were obtained by Western blotting. Activation of relevant downstream signaling pathways was assessed by immunofluorescence in confocal microscopy and by Western blot analysis. Functional outcomes were confirmed with bulk and single cell proliferation assays and motility measurements. In non-confluent (sparse) cultures PDGF-BB stimulation significantly increased phosphorylation of tyr716 specific for the Ras/MAPK pathway and tyr751 specific for the phosphoinositide 3-kinase/Akt pathway. As cell monolayers reached confluence, tyr771 and tyr1021 were the prominently phosphorylated residues. Tyr771 serves as adaptor for RasGAP, which inactivates the MAPK pathway, and tyr1021 feeds into the phospholipase Cgamma / PKC pathway. Coherent with this, MAPK phosphorylation, Ki67 positivity and proliferation dominated in dispersed cells, and could be abolished with inhibitors of the MAPK pathway. At the same time, RhoA activation, redistribution of cortactin to leading edges, and increased motility were the prominent output features in confluent cultures. Importantly, the stimulus-evoked confluence-specific changes in the phosphorylation of tyrosine residues occurred mainly in GM1-rich lipid microdomains (rafts). These observations suggest that the same stimulus is able to promote distinctly relevant signaling outputs through a confluence dependent, lipid raft-based regulatory mechanism. In particular, cell division and survival in sparse cultures and inhibition of proliferation and promotion of migration in confluent monolayers. In our model, the ability to switch the final output of the same stimulus as a function of cell density could be a key to the balance of proliferation and invasion in malignant glioblastoma.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk lipid rafts site-selective phosphorylation quantitative confocal microscopy contact inhibition tumor proliferation invasive tumor growth cell migration glioblastoma PDGFR
Megjelenés:	Cellular Signalling. - 28 : 2 (2016), p. 81-93. -
További szerzők:	Ujlaky-Nagy László (1977-) (biofizikus) Tóth Gábor (1989-) (általános orvos) Szöllősi János (1953-) (biofizikus) Vereb György (1965-) (biofizikus, orvos)
Pályázati támogatás:	K75752 OTKA NK 101337 OTKA Baross Gabor Program Egyéb
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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