title: The tyrosine kinase c-Src directly mediates growth factor-induced Notch-1 and Furin interaction and Notch-1 activation in pancreatic cancer cells.
abstract: The proteolytic activity of Furin responsible for processing full length Notch-1 (p300) plays a critical role in Notch signaling. The amplitude and duration of Notch activity can be regulated at various points in the pathway, but there has been no report regarding regulation of the Notch-1-Furin interaction, despite its importance. In the present study, we found that the Notch-1-Furin interaction is regulated by the non-receptor tyrosine kinase, c-Src. c-Src and Notch-1 are physically associated, and this association is responsible for Notch-1 processing and activation. We also found that growth factor TGF-α, an EGFR ligand, and PDGF-BB, a PDGFR ligand, induce the Notch-1-Furin interaction mediated by c-Src. Our results support three new and provocative conclusions: (1) The association between Notch-1 and Furin is a well-regulated process; (2) Extracellular growth factor signals regulate this interaction, which is mediated by c-Src; (3) There is cross-talk between the plasma growth factor receptor-c-Src and Notch pathways. Co-localization of Notch-1 and c-Src was confirmed in xenograft tumor tissues and in the tissues of pancreatic cancer patients. Our findings have implications for the mechanism by which the Notch and growth factor receptor-c-Src signaling pathways regulate carcinogenesis and cancer cell growth.
authors.affiliation: Department of Biochemistry and Molecular Biology, Cancer Institute, Capital Medical University, Beijing, China.
authors.forename: Yong-Chao
authors.initials: YC
authors.lastname: Ma
authors.forename: Chong
authors.initials: C
authors.lastname: Shi
authors.forename: Yao-Nan
authors.initials: YN
authors.lastname: Zhang
authors.forename: Lan-Ge
authors.initials: LG
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Hong-Ti
authors.initials: HT
authors.lastname: Jia
authors.forename: Yu-Xiang
authors.initials: YX
authors.lastname: Zhang
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Ze-Sheng
authors.initials: ZS
authors.lastname: Wang
mesh_terms: D000818:Animals; D000077214:Becaplermin; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C412373:AG 1879; D036341:Intercellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D051881:Receptor, Notch1; D016211:Transforming Growth Factor alpha; D000077214:Becaplermin; D019061:src-Family Kinases; D045683:Furin