Histidine-domain-containing protein tyrosine phosphatase regulates platelet-derived growth factor receptor intracellular sorting and degradation
2015 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 27, no 11, 2209-2219 p.Article in journal (Refereed) Published
Histidine domain-containing protein tyrosine phosphatase (HD-PTP) is a putative phosphatase that has been shown to affect the signaling and downregulation of certain receptor tyrosine kinases. To investigate if HD-PTP affects platelet-derived growth factor receptor beta (PDGFR beta) signaling, we employed the overexpression of HA-tagged HD-PTP, as well as siRNA-mediated and lentivirus shRNA-mediated silencing of HD-PTP in NIH3T3 cells. We found that HD-PTP was recruited to the PDGFR beta in a ligand-dependent manner. Depletion of HD-PTP resulted in an inability of PDGF-BB to promote tyrosine phosphorylation of the ubiquitin ligases c-Cbl and Cbl-b, with a concomitant missorting and reduction of the degradation of activated PDGFRS. In contrast, ligand-induced internalization of PDGFR beta was unaffected by HD-FTP silencing. Furthermore, the levels of STAM and Hrs of the ESCRT0 machinery were decreased, and immunofluorescence staining showed that in HD-PTP-depleted cells, PDGFR beta accumulated in large aberrant intracellular structures. After the reduction of HD-PTP expression, an NIH3T3-derived cell line that has autocrine PDGF-BB signaling (sis-3 T3) showed increased ability of anchorage-independent growth. However, exogenously added PDGF-BB promoted efficient additional colony formation in control cells, but was not able to do so in HD-PTP-depleted cells. Furthermore, cells depleted of HD-PTP migrated faster than control cells. In summary, HD-PTP affects the intracellular sorting of activated PDGFRS and the migration, proliferation and tumorigenicity of cells stimulated by PDGF.
Place, publisher, year, edition, pages
2015. Vol. 27, no 11, 2209-2219 p.
HD-PTP, PDGFR beta, STAT3, c-Cbl, Cbl-b, PLC gamma, ESCRT, Ubiquitination
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
IdentifiersURN: urn:nbn:se:uu:diva-264805DOI: 10.1016/j.cellsig.2015.07.020ISI: 000361777500008PubMedID: 26232618OAI: oai:DiVA.org:uu-264805DiVA: diva2:866293
FunderSwedish Cancer Society, 130519