Downregulation of platelet-derived growth factor receptor-beta in Shp-2 mutant fibroblast cell lines.
The SH2-containing tyrosine phosphatase Shp-2 appears to function downstream of a variety of growth factor receptors and might play a positive role in cell proliferation. Here we report that expression of the beta subunit of platelet-derived growth factor receptor (PDGFR-beta) was specifically downregulated in mutant fibroblasts lacking a functional Shp-2, while the levels of PDGFR-alpha EGFR and IGFIR were not changed. PDGF-stimulated DNA synthesis and extracellular signal regulated kinase (Erk) activation was severely suppressed in mutant cells. RasGAP, that responds to activation of PDGFR-beta but not PDGFR-alpha, was not phosphorylated on tyrosine in mutant cells upon PDGF-treatment. Northern blot analysis failed to detect PDGFR-beta mRNA in mutant cells. The transcription initiation from the PDGFR-beta gene promoter was not significantly changed, but the half-life of its mRNA was shortened in Shp-2 mutant cells. These observations indicate that Shp-2 not only participates in transmission of signals from growth factor receptors but also plays a specific role in the control of the PDGFR-beta expression. We propose that this is an important mechanism for the positive control of cell proliferation by Shp-2.
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Department of Biochemistry and Molecular Biology, and Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202-5121, USA.
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D000818:Animals; D000077214:Becaplermin; D002460:Cell Line; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000378:metabolism / Q000494:pharmacology; D016296:Mutagenesis; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases