Abstract
The low molecular weight phosphotyrosine phosphatase (LMW-PTP) is an enzyme that is involved in the early events of platelet-derived growth factor (PDGF) receptor signal transduction. Our previous results have shown that LMW-PTP is able to specifically bind and dephosphorylate activated PDGF receptor, thus modulating PDGF-induced mitogenesis. In particular LMW-PTP is involved in pathways that regulate the transcription of the immediately early genes myc and fos in response to growth factor stimulation. In this study we have established that, in nontransformed NIH3T3 cells, LMW-PTP exists constitutively in cytosolic and cytoskeleton-associated localization and that, after PDGF stimulation, c-Src is able to bind and to phosphorylate LMW-PTP only in the cytoskeleton-associated fraction. As a consequence of its tyrosine phosphorylation, LMW-PTP significantly increases its catalytic activity. After PDGF stimulation these two LMW-PTP pools act on distinct substrates, contributing in different manners to the PDGF receptor signaling. The cytoplasmic LMW-PTP fraction exerts its well known action on activated PDGF receptor. On the other hand we have now demonstrated that the cytoskeleton-associated LMW-PTP acts specifically on a few not yet identified proteins that become tyrosine-phosphorylated in response to the PDGF receptor activation. Finally, these two LMW-PTP pools markedly differ in the timing of the processes in which they are involved. The cytoplasmic LMW-PTP pool exerts its action within a few minutes from PDGF receptor activation (short term action), while tyrosine phosphorylation of cytoskeleton-associated LMW-PTP lasts for more than 40 min (long term action). In conclusion LMW-PTP is a striking example of an enzyme that exerts different functions and undergoes different regulation in consequence of its subcellular localization.
Highlights
Signal transduction cascades driven by tyrosine phosphorylation regulate many cellular processes in eukaryotes such as cell proliferation, differentiation, and migration [1, 2]
To assess if low molecular weight phosphotyrosine phosphatase (LMW-PTP) action is restricted to cytosolic soluble fraction or not, we have evaluated the relative amount LMW-PTP in RIPA and Complete RIPA lysis buffer (cRIPA) fractions after platelet-derived growth factor (PDGF) stimulation
We have shown that LMW-PTP is a key intermediate in the early steps of PDGF-R signal transduction, because it binds directly to activated receptor and modulates the activation of Src tyrosine kinase and the phosphorylation state of STAT proteins
Summary
Signal transduction cascades driven by tyrosine phosphorylation regulate many cellular processes in eukaryotes such as cell proliferation, differentiation, and migration [1, 2]. In this study we have established that, in nontransformed NIH3T3 cells, LMW-PTP exists constitutively in cytosolic and cytoskeleton-associated localization and that, after PDGF stimulation, c-Src is able to bind and to phosphorylate LMW-PTP only in the cytoskeletonassociated fraction.
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