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J Biol Chem, Vol. 273, Issue 12, 6776-6785, March 20, 1998
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From the 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-
Dipartimento di Scienze Biochimiche, viale
Morgagni 50, 50134 Firenze, Italy and § Istituto di Medicina
Interna, Università di Firenze, viale Morgagni 85, 50134, Firenze, Italy
1, 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.
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