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New perspectives in PDGF receptor downregulation: the main role of phosphotyrosine phosphatases

Department of Biochemical Sciences of the University of Florence, Italy

^* Author for correspondence (e-mail: paola.chiarugi{at}unifi.it )

Accepted 27 February 2002

Uncontrolled activation of receptor tyrosine kinases (RTKs) is implicated in the proliferation of cancerous cells, and deficiencies in RTKs results in pathological conditions such as developmental abnormalities and immunodeficiencies. Tight regulation of RTK cascades is therefore critical for eliciting an appropriate type and level of response to external stimuli. The aim of this work is to compare different RTK downregulation mechanisms, such as ligandinduced internalisation, ubiquitin-mediated proteolysis and dephosphorylation by protein phosphotyrosine phosphatase (PTPs). We choose platelet-derived growth factor receptor (PDGF-r) in NIH3T3 cells as a model of RTK. Our data suggest that PDGF-r internalisation could be mainly considered as a positive signaling system, as it is involved in MAPK activation rather than a downregulation of the mitotic signal. Inhibition of receptor ubiquitination does not result in regulation of PDGF-r tyrosine phosphorylation and does not lead to variation of intracellular signalling pathways. The overall PDGF-r protein degradation upon PDGF stimulation does not exceed 30-40% of the total receptor; thus the receptor remains functionally active for further stimulation. On the contrary, PTP-dependent dephosphorylation of the activated receptors appears to play a crucial role. In fact, inhibition of PTP upon PDGF stimulation results in upregulation of receptor phosphorylation level, of PI3K recruitment and activation and of cell cycle rate. On the contrary, PTP-dependent dephosphorylation does not affect the endosomic pool of activated receptor. Furthermore, we demonstrate that PDGF-r downregulation by means of PTP dephosphorylation is important for both short term (2 hours) and long-lasting (up to 8 hours) PDGF-r activation. Herein we propose a revisited model of PDGF-r downregulation in which PTPs dephosphorylation retains a major role, conferring on receptor internalisation a signal transduction function.

Key words: Phosphotyrosine phosphatases, Tyrosine kinase receptor downregulation, Endocytosis, Ubiquitination, Redox regulation

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