PMID- 10613738
OWN - NLM
STAT- MEDLINE
DCOM- 20000113
LR  - 20181130
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 31
IP  - 1
DP  - 2000 Jan
TI  - Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on ras in 
      human hepatic stellate cells.
PG  - 131-40
AB  - 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-beta receptor to FAK in human HSCs, 
      and that signaling molecules requiring geranylgeranylation may also be involved 
      in this process.
FAU - Carloni, V
AU  - Carloni V
AD  - Dipartimento di Medicina Interna, Universita di Firenze, Florence, Italy. 
      v.carloni@dfc.unifi.it
FAU - Pinzani, M
AU  - Pinzani M
FAU - Giusti, S
AU  - Giusti S
FAU - Romanelli, R G
AU  - Romanelli RG
FAU - Parola, M
AU  - Parola M
FAU - Bellomo, G
AU  - Bellomo G
FAU - Failli, P
AU  - Failli P
FAU - Hamilton, A D
AU  - Hamilton AD
FAU - Sebti, S M
AU  - Sebti SM
FAU - Laffi, G
AU  - Laffi G
FAU - Gentilini, P
AU  - Gentilini P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (Proto-Oncogene Proteins c-sis)
RN  - 1B56C968OA (Becaplermin)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - EC 2.5.- (Alkyl and Aryl Transferases)
RN  - EC 2.5.1.- (geranylgeranyltransferase type-I)
RN  - EC 2.5.1.29 (Farnesyltranstransferase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptors, Platelet-Derived Growth Factor)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 3.1.4.- (Type C Phospholipases)
RN  - EC 3.6.5.2 (HRAS protein, human)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Alkyl and Aryl Transferases/antagonists & inhibitors
MH  - Becaplermin
MH  - Calcium/metabolism
MH  - Cell Adhesion Molecules/analysis/*metabolism
MH  - Cells, Cultured
MH  - Enzyme Inhibitors/pharmacology
MH  - Farnesyltranstransferase
MH  - Focal Adhesion Kinase 1
MH  - Focal Adhesion Protein-Tyrosine Kinases
MH  - Humans
MH  - Liver/*enzymology
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mutation
MH  - Phosphorylation
MH  - Phosphotyrosine/*metabolism
MH  - Platelet-Derived Growth Factor/*pharmacology
MH  - Protein Prenylation
MH  - Protein-Tyrosine Kinases/analysis/*metabolism
MH  - Proto-Oncogene Proteins c-sis
MH  - Proto-Oncogene Proteins p21(ras)/genetics/*physiology
MH  - Receptors, Platelet-Derived Growth Factor/analysis/metabolism
MH  - Signal Transduction
MH  - Transfection
MH  - Type C Phospholipases/metabolism
EDAT- 1999/12/29 00:00
MHDA- 1999/12/29 00:01
CRDT- 1999/12/29 00:00
PHST- 1999/12/29 00:00 [pubmed]
PHST- 1999/12/29 00:01 [medline]
PHST- 1999/12/29 00:00 [entrez]
AID - S0270913900329974 [pii]
AID - 10.1002/hep.510310121 [doi]
PST - ppublish
SO  - Hepatology. 2000 Jan;31(1):131-40. doi: 10.1002/hep.510310121.