Independence of angiotensin II-induced MAP kinase activation from angiotensin type 1 receptor internalization in clone 9 hepatocytes

Mol Endocrinol. 2002 Mar;16(3):610-20. doi: 10.1210/mend.16.3.0781.


The agonist-induced internalization of several G protein-coupled receptors is an obligatory requirement for their activation of MAPKs. Studies on the relationship between endocytosis of the angiotensin II (Ang II) type 1 receptor (AT1-R) and Ang II-induced ERK1/2 activation were performed in clone 9 (C9) rat hepatic cells treated with inhibitors of endocytosis [sucrose, phenylarsine oxide (PAO), and concanavalin A]. Although Ang II-induced endocytosis of the AT1-R was prevented by sucrose and PAO, and was partially inhibited by concanavalin A, there was no impairment of Ang II-induced ERK activation. However, the specific epidermal growth factor receptor (EGF-R) kinase inhibitor, AG1478, abolished Ang II-induced activation of ERK1/2. Sucrose and PAO also inhibited EGFinduced internalization of the EGF-R in C9 cells, and the inability of these agents to impair EGF-induced ERK activation suggested that the latter is also independent of receptor endocytosis. In COS-7 cells transiently expressing the rat AT1A-R, Ang II also caused ERK activation through EGF-R transactivation. Furthermore, a mutant AT1A-R with truncated carboxyl terminus and impaired internalization retained full ability to activate ERK1/2 in response to Ang II stimulation. These findings demonstrate that Ang II-induced ERK1/2 activation in C9 hepatocytes is independent of both AT1-R and EGF-R endocytosis and is mediated by transactivation of the EGF-R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Arsenicals / pharmacology
  • COS Cells
  • Cell Line
  • Concanavalin A / pharmacology
  • Endocytosis / drug effects
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • Gene Expression
  • Hepatocytes / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Protein Kinase Inhibitors
  • Quinazolines
  • Rats
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin / genetics
  • Receptors, Angiotensin / metabolism*
  • Sucrose / pharmacology
  • Transfection
  • Tyrphostins / pharmacology


  • Arsenicals
  • Enzyme Inhibitors
  • Protein Kinase Inhibitors
  • Quinazolines
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin
  • Tyrphostins
  • oxophenylarsine
  • Concanavalin A
  • Angiotensin II
  • RTKI cpd
  • Sucrose
  • Epidermal Growth Factor
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases