Abstract
Recent reports have described several cellular phenotypes that appear to be mediated by Endosialin/TEM-1/CD248 (TEM-1), including tubule formation on matrigel, migration and proliferation. It has been shown that siRNA knock-down of TEM-1 in primary human fibroblasts resulted in reduced proliferation. However, the downstream signaling events that mediate TEM-1 function(s) currently remain unknown. In this study, we demonstrate that TEM-1 mediates proliferation of primary human pericytes through a PDGF receptor signaling pathway. Normal pericytes expressing high levels of TEM-1 were able to proliferate, respond to PDGF-BB stimulation by phosphorylating both the PDGF receptor and the MAP kinase ERK-1/2, and induce the expression of the immediate early transcription factor c-Fos. However, when TEM-1 expression was knocked-down, PDGF-BB-induced proliferation, ERK-1/2 phosphorylation, and c-Fos expression were significantly impaired. Thus, our results provide evidence for a TEM-1-dependent signal pathway that controls proliferation of human pericytes and suggest targeting this pathway for future strategies aimed at mitigating tumor angiogenesis.
MeSH terms
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism*
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Becaplermin
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Blotting, Western
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Cell Line
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Cell Proliferation*
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Gene Expression / drug effects
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Humans
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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Pericytes / cytology
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Pericytes / drug effects
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Pericytes / metabolism*
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Phosphorylation / drug effects
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Platelet-Derived Growth Factor / pharmacology
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Proto-Oncogene Proteins c-sis
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RNA Interference
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Receptors, Platelet-Derived Growth Factor / genetics
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Receptors, Platelet-Derived Growth Factor / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
Substances
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Antigens, CD
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Antigens, Neoplasm
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CD248 protein, human
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-sis
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Becaplermin
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Receptors, Platelet-Derived Growth Factor
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3