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 (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.
Chiarugi
Paola
P
Department of Biochemical Sciences, University of Florence, 50134 Florence, Italy.
Cirri
Paolo
P
Taddei
Maria Letizia
ML
Giannoni
Elisa
E
Fiaschi
Tania
T
Buricchi
Francesca
F
Camici
Guido
G
Raugei
Giovanni
G
Ramponi
Giampietro
G
D016475:3T3 Cells; D000818:Animals; D000077214:Becaplermin; D001692:Biological Transport; D002455:Cell Division / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism* / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014357:Trypsin; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D000077214:Becaplermin; D019000:Phosphotyrosine; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor; D054648:Protein Phosphatase 2; C490429:ACP1 protein, human; C490428:Acp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; D014357:Trypsin