title: The tyrosine phosphatase SHP-1 inhibits proliferation of activated hepatic stellate cells by impairing PDGF receptor signaling.
abstract: The dimerization and auto-transphosphorylation of platelet-derived growth factor receptor (PDGFR) upon engagement by platelet-derived growth factor (PDGF) activates signals promoting the mitogenic response of hepatic stellate cells (HSCs) due to liver injury, thus contributing to the development of hepatic fibrosis. We demonstrate that the tyrosine phosphatases Src homology 2 domain-containing phosphatase 1 and 2 (SHP-1 and SHP-2) act as crucial regulators of a complex signaling network orchestrated by PDGFR activation in a spatio-temporal manner with diverse and opposing functions in HSCs. In fact, silencing of either phosphatase shows that SHP-2 is committed to PDGFR-mediated cell proliferation, whereas SHP-1 dephosphorylates PDGFR hence abrogating the downstream signaling pathways that result in HSC activation. In this regard, SHP-1 as an off-switch of PDGFR signaling appears to emerge as a valuable molecular target to trigger as to prevent HSC proliferation and the fibrogenic effects of HSC activation. We show that boswellic acid, a multitarget compound with potent anti-inflammatory action, exerts an anti-proliferative effect on HSCs, as in other cell models, by upregulating SHP-1 with subsequent dephosphorylation of PDGFR-β and downregulation of PDGF-dependent signaling after PDGF stimulation. Moreover, the synergism resulting from the combined use of boswellic acid and imatinib, which directly inhibits PDGFR-β activity, on activated HSCs offers new perspectives for the development of therapeutic strategies that could implement molecules affecting diverse players of this molecular circuit, thus paving the way to multi-drug low-dose regimens for liver fibrosis.
authors.affiliation: Department of Molecular Medicine, University of Padua, Viale G. Colombo 3, 35131 Padua, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tibaldi
authors.affiliation: Department of Molecular Medicine, University of Padua, Viale G. Colombo 3, 35131 Padua, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zonta
authors.affiliation: Department of Molecular Medicine, University of Padua, Viale G. Colombo 3, 35131 Padua, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Bordin
authors.affiliation: Department of Molecular Medicine, University of Padua, Viale G. Colombo 3, 35131 Padua, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Magrin
authors.affiliation: Department of Surgical and Gastroenterological Sciences, University of Padua, Via Giustiniani 2, 35128 Padua, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Gringeri
authors.affiliation: Department of Surgical and Gastroenterological Sciences, University of Padua, Via Giustiniani 2, 35128 Padua, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Cillo
authors.affiliation: Department of Medical Specialties, Hospital of Cittadella, Via Casa di Ricovero 40, 35013 Padua, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Idotta
authors.affiliation: Department of Molecular Medicine, University of Padua, Viale G. Colombo 3, 35131 Padua, Italy. Electronic address: mario.pagano@unipd.it.
authors.forename: Mario Angelo
authors.initials: MA
authors.lastname: Pagano
authors.affiliation: Department of Molecular Medicine, University of Padua, Viale G. Colombo 3, 35131 Padua, Italy. Electronic address: annamaria.brunati@unipd.it.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Brunati
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001549:Benzamides / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology
chemical_list: D001549:Benzamides; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D014315:Triterpenes; D000077214:Becaplermin; C054625:boswellic acid; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6
keywords: Hepatic stellate cell; Liver fibrosis; PDGF receptor; Protein tyrosine phosphatase; SHP-1; Tyrosine phosphorylation