Role of the adenylate cyclase, phosphoinositidase C and receptor tyrosyl kinase systems in the control of hepatocyte proliferation by hepatocyte growth factor

A J Marker, E Galloway, S Palmer, T Nakamura, G W Gould, R N MacSween, M Bushfield

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Hepatocyte growth factor (HGF) is the most potent known mitogen for hepatocytes in primary culture. However, the mechanisms through which HGF induces hepatocyte proliferation have not been defined. Here we have investigated the role of the adenylate cyclase, phosphoinositidase C and tyrosine kinase signalling systems in the control of hepatocyte proliferation by HGF using freshly isolated or cultured adult rat hepatocytes. We show that human recombinant HGF caused a dose-dependent increase in hepatocyte DNA synthesis with a maximal effect at 10 ng/mL and an EC50 of 5.9 ng/mL. HGF had no effect on hepatocyte adenylate cyclase activity or intracellular cAMP levels. Elevation of hepatocyte cAMP levels resulted in inhibition of HGF-stimulated DNA synthesis. HGF stimulated inositol phospholipid hydrolysis with a maximal effect at 25 ng/mL and potentiated the effect of vasopressin (10(-8) and 10(-9)M). HGF (100 ng/mL) caused an increase in the phosphorylation on tyrosine of an unknown hepatocyte protein with a molecular mass of 36 kDa. Thus, we have shown that HGF, like epidermal growth factor (EGF), can activate the phosphoinositidase C and tyrosine kinase systems in rat hepatocytes. As with EGF, these intracellular signalling systems may underlie HGF-induced hepatocyte proliferation.

Original languageEnglish
Pages (from-to)1037-43
Number of pages7
JournalBiochemical Pharmacology
Volume44
Issue number6
DOIs
Publication statusPublished - 25 Sep 1992

Fingerprint

Hepatocyte Growth Factor
Adenylyl Cyclases
Hepatocytes
Phosphotransferases
Epidermal Growth Factor
Protein-Tyrosine Kinases
Rats
glycerophosphoinositol glycerophosphodiesterase
Phosphorylation
DNA
Molecular mass
Phosphatidylinositols
Vasopressins
Mitogens
Tyrosine
Hydrolysis

Keywords

  • adenylate cyclase
  • animals
  • cell division
  • Cells, Cultured
  • cyclic amp
  • DNA
  • enzyme activation
  • hepatectomy
  • hepatocyte growth factor
  • inositol phosphates
  • liver
  • liver regeneration
  • male
  • phosphoric diester hydrolases
  • phosphorylation
  • protein-tyrosine kinases
  • rats

Cite this

Marker, A J ; Galloway, E ; Palmer, S ; Nakamura, T ; Gould, G W ; MacSween, R N ; Bushfield, M. / Role of the adenylate cyclase, phosphoinositidase C and receptor tyrosyl kinase systems in the control of hepatocyte proliferation by hepatocyte growth factor. In: Biochemical Pharmacology. 1992 ; Vol. 44, No. 6. pp. 1037-43.
@article{d53c138230f54387a899121cd1c26b8b,
title = "Role of the adenylate cyclase, phosphoinositidase C and receptor tyrosyl kinase systems in the control of hepatocyte proliferation by hepatocyte growth factor",
abstract = "Hepatocyte growth factor (HGF) is the most potent known mitogen for hepatocytes in primary culture. However, the mechanisms through which HGF induces hepatocyte proliferation have not been defined. Here we have investigated the role of the adenylate cyclase, phosphoinositidase C and tyrosine kinase signalling systems in the control of hepatocyte proliferation by HGF using freshly isolated or cultured adult rat hepatocytes. We show that human recombinant HGF caused a dose-dependent increase in hepatocyte DNA synthesis with a maximal effect at 10 ng/mL and an EC50 of 5.9 ng/mL. HGF had no effect on hepatocyte adenylate cyclase activity or intracellular cAMP levels. Elevation of hepatocyte cAMP levels resulted in inhibition of HGF-stimulated DNA synthesis. HGF stimulated inositol phospholipid hydrolysis with a maximal effect at 25 ng/mL and potentiated the effect of vasopressin (10(-8) and 10(-9)M). HGF (100 ng/mL) caused an increase in the phosphorylation on tyrosine of an unknown hepatocyte protein with a molecular mass of 36 kDa. Thus, we have shown that HGF, like epidermal growth factor (EGF), can activate the phosphoinositidase C and tyrosine kinase systems in rat hepatocytes. As with EGF, these intracellular signalling systems may underlie HGF-induced hepatocyte proliferation.",
keywords = "adenylate cyclase, animals, cell division, Cells, Cultured, cyclic amp, DNA, enzyme activation, hepatectomy, hepatocyte growth factor, inositol phosphates, liver, liver regeneration, male, phosphoric diester hydrolases, phosphorylation, protein-tyrosine kinases, rats",
author = "Marker, {A J} and E Galloway and S Palmer and T Nakamura and Gould, {G W} and MacSween, {R N} and M Bushfield",
year = "1992",
month = "9",
day = "25",
doi = "10.1016/0006-2952(92)90365-P",
language = "English",
volume = "44",
pages = "1037--43",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
number = "6",

}

Role of the adenylate cyclase, phosphoinositidase C and receptor tyrosyl kinase systems in the control of hepatocyte proliferation by hepatocyte growth factor. / Marker, A J; Galloway, E; Palmer, S; Nakamura, T; Gould, G W; MacSween, R N; Bushfield, M.

In: Biochemical Pharmacology, Vol. 44, No. 6, 25.09.1992, p. 1037-43.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of the adenylate cyclase, phosphoinositidase C and receptor tyrosyl kinase systems in the control of hepatocyte proliferation by hepatocyte growth factor

AU - Marker, A J

AU - Galloway, E

AU - Palmer, S

AU - Nakamura, T

AU - Gould, G W

AU - MacSween, R N

AU - Bushfield, M

PY - 1992/9/25

Y1 - 1992/9/25

N2 - Hepatocyte growth factor (HGF) is the most potent known mitogen for hepatocytes in primary culture. However, the mechanisms through which HGF induces hepatocyte proliferation have not been defined. Here we have investigated the role of the adenylate cyclase, phosphoinositidase C and tyrosine kinase signalling systems in the control of hepatocyte proliferation by HGF using freshly isolated or cultured adult rat hepatocytes. We show that human recombinant HGF caused a dose-dependent increase in hepatocyte DNA synthesis with a maximal effect at 10 ng/mL and an EC50 of 5.9 ng/mL. HGF had no effect on hepatocyte adenylate cyclase activity or intracellular cAMP levels. Elevation of hepatocyte cAMP levels resulted in inhibition of HGF-stimulated DNA synthesis. HGF stimulated inositol phospholipid hydrolysis with a maximal effect at 25 ng/mL and potentiated the effect of vasopressin (10(-8) and 10(-9)M). HGF (100 ng/mL) caused an increase in the phosphorylation on tyrosine of an unknown hepatocyte protein with a molecular mass of 36 kDa. Thus, we have shown that HGF, like epidermal growth factor (EGF), can activate the phosphoinositidase C and tyrosine kinase systems in rat hepatocytes. As with EGF, these intracellular signalling systems may underlie HGF-induced hepatocyte proliferation.

AB - Hepatocyte growth factor (HGF) is the most potent known mitogen for hepatocytes in primary culture. However, the mechanisms through which HGF induces hepatocyte proliferation have not been defined. Here we have investigated the role of the adenylate cyclase, phosphoinositidase C and tyrosine kinase signalling systems in the control of hepatocyte proliferation by HGF using freshly isolated or cultured adult rat hepatocytes. We show that human recombinant HGF caused a dose-dependent increase in hepatocyte DNA synthesis with a maximal effect at 10 ng/mL and an EC50 of 5.9 ng/mL. HGF had no effect on hepatocyte adenylate cyclase activity or intracellular cAMP levels. Elevation of hepatocyte cAMP levels resulted in inhibition of HGF-stimulated DNA synthesis. HGF stimulated inositol phospholipid hydrolysis with a maximal effect at 25 ng/mL and potentiated the effect of vasopressin (10(-8) and 10(-9)M). HGF (100 ng/mL) caused an increase in the phosphorylation on tyrosine of an unknown hepatocyte protein with a molecular mass of 36 kDa. Thus, we have shown that HGF, like epidermal growth factor (EGF), can activate the phosphoinositidase C and tyrosine kinase systems in rat hepatocytes. As with EGF, these intracellular signalling systems may underlie HGF-induced hepatocyte proliferation.

KW - adenylate cyclase

KW - animals

KW - cell division

KW - Cells, Cultured

KW - cyclic amp

KW - DNA

KW - enzyme activation

KW - hepatectomy

KW - hepatocyte growth factor

KW - inositol phosphates

KW - liver

KW - liver regeneration

KW - male

KW - phosphoric diester hydrolases

KW - phosphorylation

KW - protein-tyrosine kinases

KW - rats

UR - http://www.ncbi.nlm.nih.gov/pubmed/1329755

U2 - 10.1016/0006-2952(92)90365-P

DO - 10.1016/0006-2952(92)90365-P

M3 - Article

VL - 44

SP - 1037

EP - 1043

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 6

ER -