title: Crosstalk between the urokinase-type plasminogen activator receptor and EGF receptor variant III supports survival and growth of glioblastoma cells.
abstract: A truncated and constitutively active form of the EGF receptor, variant III (EGFRvIII), is a major determinant of tumor growth and progression in glioblastoma multiforme (GBM). Extensive bidirectional crosstalk occurs in the cell-signaling pathways downstream of the EGFR and the urokinase-type plasminogen activator receptor (uPAR); however, crosstalk between EGFRvIII and uPAR has not been examined. Here, we show that uPAR does not regulate ERK activation in EGFRvIII-expressing GBM cells; however, in GBM cells isolated from four separate xenografts in which EGFRvIII expression was down-regulated in vivo, uPAR assumed a major role in sustaining ERK activation. Phosphorylation of Tyr-845 in the EGFR, which is mediated by Src family kinases, depended on uPAR in EGFRvIII-expressing GBM cells. Activation of the mitogenic and prosurvival transcription factor, STAT5b, downstream of EGFRvIII, also required uPAR. The EGFR-selective tyrosine kinase inhibitors, erlotinib and gefitinib, blocked not only EGFRvIII signaling to ERK but also uPAR-dependent STAT5b activation. uPAR gene silencing in EGFRvIII-expressing GBM cells and in cells from tumors that escaped dependency on EGFRvIII decreased cell survival and proliferation. Xenografts of EGFRvIII-expressing cancer cell lines and a human GBM, which was propagated as a xenograft, were robustly immunopositive for uPAR and phospho-Tyr-845 by immunohistochemistry. A human GBM in which the EGFR gene was amplified without truncation was immunonegative for both uPAR and phospho-Tyr-845. These studies identify distinct cell-signaling activities for uPAR in GBM cells that express EGFRvIII and in cells released from dormancy when EGFRvIII is neutralized. uPAR and its crosstalk pathways with EGFRvIII emerge as logical targets for therapeutics development in GBM.
authors: Department of Pathology, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Jingjing
authors: J
authors: Hu
authors: Minji
authors: M
authors: Jo
authors: Webster K
authors: WK
authors: Cavenee
authors: Frank
authors: F
authors: Furnari
authors: Scott R
authors: SR
authors: VandenBerg
authors: Steven L
authors: SL
authors: Gonias
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004317:Doxorubicin / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D020239:Receptor Cross-Talk; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014183:Transplantation, Heterologous; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D055293:Receptors, Urokinase Plasminogen Activator; D050799:STAT5 Transcription Factor; C410723:epidermal growth factor receptor VIII; D014443:Tyrosine; D004317:Doxorubicin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib