The tyrosine phosphatase SHP-1 inhibits proliferation of activated hepatic stellate cells by impairing PDGF receptor signaling

Biochim Biophys Acta. 2014 Feb;1843(2):288-98. doi: 10.1016/j.bbamcr.2013.10.010. Epub 2013 Oct 18.


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.

Keywords: Hepatic stellate cell; Liver fibrosis; PDGF receptor; Protein tyrosine phosphatase; SHP-1; Tyrosine phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin
  • Benzamides / pharmacology
  • Cell Membrane / drug effects
  • Cell Membrane / enzymology
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Hepatic Stellate Cells / cytology*
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / enzymology*
  • Imatinib Mesylate
  • Male
  • Piperazines / pharmacology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Proto-Oncogene Proteins c-sis / pharmacology
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Platelet-Derived Growth Factor / metabolism*
  • Signal Transduction* / drug effects
  • Triterpenes / pharmacology


  • Benzamides
  • Piperazines
  • Proto-Oncogene Proteins c-sis
  • Pyrimidines
  • Triterpenes
  • Becaplermin
  • boswellic acid
  • Imatinib Mesylate
  • Receptors, Platelet-Derived Growth Factor
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6