The Src and signal transducers and activators of transcription pathways as specific targets for low molecular weight phosphotyrosine-protein phosphatase in platelet-derived growth factor signaling.
The low molecular weight phosphotyrosine-protein phosphatase (LMW-PTP) is a cytosolic phosphotyrosine-protein phosphatase specifically interacting with the activated platelet-derived growth factor (PDGF) receptor through its active site. Overexpression of the LMW-PTP results in modulation of PDGF-dependent mitogenesis. In this study we investigated the effects of this tyrosine phosphatase on the signaling pathways relevant for PDGF-dependent DNA synthesis. NIH 3T3 cells were stably transfected with active or dominant negative LMW-PTP. The effects of LMW-PTP were essentially restricted to the G1 phase of the cell cycle. Upon stimulation with PDGF, cells transfected with the dominant negative LMW-PTP showed an increased activation of Src, whereas the active LMW-PTP induced a reduced activation of this proto-oncogene. We observe that c-Src binding to PDGF receptor upon stimulation is prevented by overexpression of LMW-PTP. These effects were associated with parallel changes in myc expression. Moreover, wild-type and dominant negative LMW-PTP differentially regulated STAT1 and STAT3 activation and tyrosine phosphorylation, whereas they did not modify extracellular signal-regulated kinase activity. However, these modifications were associated with changes in fos expression despite the lack of any effect on extracellular signal-regulated kinase activation. Other independent pathways involved in PDGF-induced mitogenesis, such as phosphatidylinositol 3-kinase and phospholipase C-gamma1, were not affected by LMW-PTP. These data indicate that this phosphatase selectively interferes with the Src and the STATs pathways in PDGF downstream signaling. The resulting changes in myc and fos proto-oncogene expression are likely to mediate the modifications observed in the G1 phase of the cell cycle.
Chiarugi
P
P
Dipartimento di Scienze Biochimiche, viale Morgagni 50, 50134 Firenze, Italy.
Cirri
P
P
Marra
F
F
Raugei
G
G
Fiaschi
T
T
Camici
G
G
Manao
G
G
Romanelli
R G
RG
Ramponi
G
G
D016475:3T3 Cells; D000818:Animals; D002633:Chemotaxis; D004268:DNA-Binding Proteins / Q000378:metabolism; D016193:G1 Phase; D051379:Mice; D008970:Molecular Weight; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D010982:Platelet-Derived Growth Factor; D016271:Proto-Oncogene Proteins c-myc; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D017479:Receptors, Platelet-Derived Growth Factor; D015688:Oncogene Protein pp60(v-src); D017027:Protein Tyrosine Phosphatases