Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on Ras in human hepatic stellate cells

Vlnicio Carloni, Massimo Plnzani, Sabrina Glusti, Roberto G. Romanelli, Maurizio Parola, Glorgio Bellomo, Paola Failli, Andrew Hamilton, Said M. Sebti, Giacomo Laffi, Paolo Gentilini

Research output: Contribution to journalArticle

Abstract

Focal adhesion kinase (FAK) is a widely expressed nonreceptor tyrosine kinase found in focal adhesions. FAK has been indicated as a point of convergence of other signaling pathways including platelet-derived growth factor (PDGF) receptors, and recently, FAK tyrosine phosphorylation has been shown to be stimulated by PDGF. In the present study we assessed the role of Ras as a possible intermediate protein regulating PDGF-induced FAK tyrosine phosphorylation in human hepatic stellate cells (HSCs), liver-specific pericytes primarily involved in the pathogenesis of liver fibrosis. For this purpose, cells were first subjected to retroviral-mediated gene transfer with a dominant-negative mutant of Ras (N17Ras). This resulted in a marked inhibition of PDGF-induced FAK tyrosine phosphorylation together with the expected reduction of PDGF-induced extracellular signal-regulated kinase activity (ERK). Afterward, the effects of pharmacological agents potentially affecting Ras isoprenylation were evaluated. PDGF-induced FAK tyrosine phosphorylation, ERK activity and intracellular calcium increase, as well as the biological effects of this growth factor, (i.e., mitogenesis and cell migration) were effectively blocked by GGTI-298, an inhibitor of geranylgeranyltransferase I. Inhibition of Ras processing obtained with FTI- 277, an inhibitor of farnesyltransferase, resulted in detectable effects only at high doses. Taken together, these results establish that Ras operates as a protein-linking PDGF-β receptor to FAK in human HscS, and that signaling molecules requiring geranylgeranylation may also be involved in this process.

Original languageEnglish (US)
Pages (from-to)131-140
Number of pages10
JournalHepatology
Volume31
Issue number1
StatePublished - 2000

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Focal Adhesion Protein-Tyrosine Kinases
Hepatic Stellate Cells
Platelet-Derived Growth Factor
Tyrosine
Phosphorylation
Prenylation
Platelet-Derived Growth Factor Receptors
Farnesyltranstransferase
Pericytes
Focal Adhesions
Extracellular Signal-Regulated MAP Kinases
Liver Cirrhosis
Protein-Tyrosine Kinases
Cell Movement
Intercellular Signaling Peptides and Proteins
Proteins
Pharmacology
Calcium
Liver
Genes

ASJC Scopus subject areas

  • Hepatology

Cite this

Carloni, V., Plnzani, M., Glusti, S., Romanelli, R. G., Parola, M., Bellomo, G., ... Gentilini, P. (2000). Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on Ras in human hepatic stellate cells. Hepatology, 31(1), 131-140.

Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on Ras in human hepatic stellate cells. / Carloni, Vlnicio; Plnzani, Massimo; Glusti, Sabrina; Romanelli, Roberto G.; Parola, Maurizio; Bellomo, Glorgio; Failli, Paola; Hamilton, Andrew; Sebti, Said M.; Laffi, Giacomo; Gentilini, Paolo.

In: Hepatology, Vol. 31, No. 1, 2000, p. 131-140.

Research output: Contribution to journalArticle

Carloni, V, Plnzani, M, Glusti, S, Romanelli, RG, Parola, M, Bellomo, G, Failli, P, Hamilton, A, Sebti, SM, Laffi, G & Gentilini, P 2000, 'Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on Ras in human hepatic stellate cells', Hepatology, vol. 31, no. 1, pp. 131-140.
Carloni V, Plnzani M, Glusti S, Romanelli RG, Parola M, Bellomo G et al. Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on Ras in human hepatic stellate cells. Hepatology. 2000;31(1):131-140.
Carloni, Vlnicio ; Plnzani, Massimo ; Glusti, Sabrina ; Romanelli, Roberto G. ; Parola, Maurizio ; Bellomo, Glorgio ; Failli, Paola ; Hamilton, Andrew ; Sebti, Said M. ; Laffi, Giacomo ; Gentilini, Paolo. / Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on Ras in human hepatic stellate cells. In: Hepatology. 2000 ; Vol. 31, No. 1. pp. 131-140.
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AU - Romanelli, Roberto G.

AU - Parola, Maurizio

AU - Bellomo, Glorgio

AU - Failli, Paola

AU - Hamilton, Andrew

AU - Sebti, Said M.

AU - Laffi, Giacomo

AU - Gentilini, Paolo

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