Proliferation versus migration in platelet-derived growth factor signaling: the key role of endocytosis.
It is common knowledge that platelet-derived growth factor (PDGF) is a critical regulator of mesenchymal cell migration and proliferation. Nevertheless, these two cellular responses are mutually exclusive. To solve this apparent contradiction, we studied the behavior of NIH3T3 fibroblasts in response to increasing concentrations of PDGF. We found that there is strong cell proliferation induction only with PDGF concentrations >5 ng/ml, whereas the cell migration response arises starting from 1 ng/ml and is negligible at higher PDGF concentrations. According to these phenotypic evidences, our data indicate that cells display a differential activation of the main signaling pathways in response to PDGF as a function of the stimulation dose. At low PDGF concentrations, there is maximal activation of signaling pathways linked to cytoskeleton rearrangement needed for cell motility, whereas high PDGF concentrations activate pathways linked to mitogenesis induction. Our results suggest a mechanism by which cells switch from a migrating to a proliferating phenotype sensing the increasing gradient of PDGF. In addition, we propose that the cell decision to proliferate or migrate relies on different endocytotic routes of the PDGF receptor in response to different PDGF concentrations.
De Donatis
Alina
A
Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Firenze, Italy.
Comito
Giusy
G
Buricchi
Francesca
F
Vinci
Maria C
MC
Parenti
Astrid
A
Caselli
Anna
A
Camici
Guido
G
Manao
Giampaolo
G
Ramponi
Giampietro
G
Cirri
Paolo
P
D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020830:rac1 GTP-Binding Protein