Abstract
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.
Highlights
Receptor tyrosine kinases regulate many aspects of cellular physiology such as proliferation, survival, migration, and differentiation [1], transducing and integrating extracellular signaling inputs coming from soluble as well as insoluble molecules
It is well known that platelet-derived growth factor (PDGF),2 interacting with its receptor on the surface of target cells, induces and regulates many physiologic and pathologic processes such as wound healing and tissue repair, tissue development and organogenesis, and cancer
PDGF exerts its multifaceted functions by binding to the PDGF receptor (PDGFR), which dimerizes, activates its intrinsic catalytic activity, and undergoes autophosphorylation on Ͼ10 specific tyrosines that serve as docking sites for intracellular signaling molecules harboring the SH2 (Src homology 2) or protein tyrosine-binding domain [3, 4], such as phosphatidylinositol 3-kinase (PI3K), phospholipase C␥, the Src family of tyrosine kinases, the SHP-2 tyrosine phosphatase, and Ras GTPase-activating protein, as well as adaptor molecules such as Grb2, Shc, Nck, Grb7, and Crk and STAT proteins
Summary
It is common knowledge that platelet-derived growth factor (PDGF) is a critical regulator of mesenchymal cell migration and proliferation These two cellular responses are mutually exclusive. There are many physiologic and pathologic situations in which a growth factor gradient can be formed, e.g. during development, wound healing, and angiogenesis, as well as in cancer growth In such conditions, target cells more distant from the gradient source sense a relatively low PDGF concentration, and their phenotypic response consists of directional cell migration along the gradient. Low PDGF doses induce clathrin-mediated endocytosis (CME), which is not sufficient per se to elicit cell proliferation In this condition, PDGFR remains prevalently on the cell surface, acting essentially as a sensor. At high PDGF concentrations, PDGFR internalization shifts, at least partially, toward a different kind of mechanism: raft/caveolin-mediated endocytosis
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