title: Intracellular signaling cascades triggered by the NK1 fragment of hepatocyte growth factor in human prostate epithelial cell line PNT1A.
abstract: Hepatocyte Growth Factor (HGF)/c-MET signaling has an emerging role in promoting cell proliferation, survival, migration, wound repair and branching in a variety of cell types. HGF plays a crucial role as a mediator of stromal-epithelial interactions in the normal prostate but the precise biological function of HGF/c-Met interaction in the normal prostate and in prostate cancer is not clear. HGF has two naturally occurring splice variants and NK1, the smallest of these HGF variants, consists of the HGF amino terminus through the first kringle domain. We evaluated the intracellular signaling cascades and the morphological changes triggered by NK1 in human prostate epithelial cell line PNT1A which shows molecular and biochemical properties close to the normal prostate epithelium. We demonstrated that these cells express a functional c-MET, and cell exposure to NK1 induces the phosphorylation of tyrosines 1313/1349/1356 residues of c-MET which provide docking sites for signaling molecules. We observed an increased phosphorylation of ERK1/2, Akt, c-Src, p125FAK, SMAD2/3, and STAT3, down-regulation of the expression of epithelial cell-cell adhesion marker E-cadherin, and enhanced expression levels of mesenchymal markers vimentin, fibronectin, vinculin, α-actinin, and α-smooth muscle actin. This results in cell proliferation, in the appearance of a mesenchymal phenotype, in morphological changes resembling cell scattering and in wound healing. Our findings highlight the function of NK1 in non-tumorigenic human prostatic epithelial cells and provide a picture of the signaling pathways triggered by NK1 in a unique cell line.
authors.affiliation: Department of Biochemistry and Medical Biotechnologies, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
authors.forename: Luigi Michele
authors.initials: LM
authors.lastname: Pavone
authors.forename: Fabio
authors.initials: F
authors.lastname: Cattaneo
authors.forename: Silviana
authors.initials: S
authors.lastname: Rea
authors.forename: Valeria
authors.initials: V
authors.lastname: De Pasquale
authors.forename: Anna
authors.initials: A
authors.lastname: Spina
authors.forename: Elena
authors.initials: E
authors.lastname: Sauchelli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mastellone
authors.forename: Rosario
authors.initials: R
authors.lastname: Ammendola
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D004847:Epithelial Cells; D058750:Epithelial-Mesenchymal Transition; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology*; D020033:Protein Isoforms / Q000494:pharmacology / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D015820:Cadherins; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3