Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation

Low molecular weight phosphotyrosine phosphatase (LMW-PTP) is an enzyme involved in platelet-derived growth factor-induced mitogenesis and cytoskeleton rearrangement. Our previous results demonstrated that LMW-PTP is able to bind and dephosphorylate activated platelet-derived growth factor receptor...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-10, Vol.277 (40), p.37331-37338
Main Authors: Chiarugi, Paola, Cirri, Paolo, Taddei, Maria Letizia, Giannoni, Elisa, Fiaschi, Tania, Buricchi, Francesca, Camici, Guido, Raugei, Giovanni, Ramponi, Giampietro
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Becaplermin
Biological Transport
Cell Division - physiology
Humans
Isoenzymes - physiology
Kinetics
Mice
Phosphorylation
Phosphotyrosine - metabolism
Platelet-Derived Growth Factor - pharmacology
Protein Phosphatase 2
Protein Tyrosine Phosphatases - physiology
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-sis
Receptors, Platelet-Derived Growth Factor - metabolism
Receptors, Platelet-Derived Growth Factor - physiology
Recombinant Proteins - pharmacology
Time Factors
Trypsin
Tumor Cells, Cultured
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Summary:Low molecular weight phosphotyrosine phosphatase (LMW-PTP) is an enzyme involved in platelet-derived growth factor-induced mitogenesis and cytoskeleton rearrangement. Our previous results demonstrated that LMW-PTP is able to bind and dephosphorylate activated platelet-derived growth factor receptor (PDGF-r), thus inhibiting cell proliferation. Here we revisit the role of LMW-PTP on activated PDGF-r dephosphorylation. We demonstrate that LMW-PTP preferentially acts on cell surface PDGF-r, excluding the internalized activated receptor pool. Many phosphotyrosine phosphatases act by site-selective dephosphorylation on several sites of PDGF-r, but until now, there has been no evidence of a direct involvement of a specific phosphotyrosine phosphatase in the dephosphorylation of the 857 kinase domain activation tyrosine. Here we report that LMW-PTP affects the kinase activity of the receptor through the binding and dephosphorylation of Tyr-857 and influences many of the signal outputs from the receptor. In particular, we demonstrate a down-regulation of phosphatidylinositol 3-kinase, Src homology phosphatase-2, and phospholipase C-gamma1 binding but not of MAPK activation. In addition, we report a slight action of LMW-PTP on Tyr-716, which directs MAPK activation through Grb2 binding. On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M205203200