The mechanism of angiotensin II-induced extracellular signal-regulated kinase-1/2 activation is independent of angiotensin AT(1A) receptor internalisation

Cell Signal. 2001 Apr;13(4):269-77. doi: 10.1016/s0898-6568(01)00135-8.


The aim of this study was to determine whether internalisation of the angiotensin II (Ang II) AT(1A) receptor (AT(1A)R) was a prerequisite for Ang II-induced activation of the extracellular signal-regulated kinases, ERK-1/2. The human embryonic kidney (HEK293) cell line stably transfected with either the wild-type rat AT(1A)R or an internalisation-deficient C-terminal truncated mutant of the AT(1A)R (AT(1A)T318R) was used as a model for these studies. Inhibition of AT(1A)R internalisation by treatment with an inhibitor of clathrin-mediated endocytosis, Concanavalin A (Con A), did not inhibit Ang II-induced ERK-1/2 activation. Furthermore, cells transfected with the internalisation-deficient AT(1A)T318R mutant readily activated ERK-1/2 in response to Ang II. Ang II activated ERK-1/2 via two distinct signalling pathways in HEK-AT(1A)R cells. Approximately half of Ang II-induced ERK-1/2 activation was protein kinase C (PKC)-dependent, and the remainder was calcium- and c-Src-dependent and involved transactivation of the epidermal growth factor receptor (EGFR). In summary, Ang II-induced activation of ERK-1/2 occurs via two distinct pathways in HEK293 cells, neither of which requires AT(1A)R internalisation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / genetics
  • Angiotensin II / metabolism*
  • Animals
  • Calcium / physiology
  • Cell Line
  • Concanavalin A / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • ErbB Receptors / metabolism
  • Humans
  • Immunoblotting
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • Mutation
  • Protein Kinase C / metabolism
  • Protein Kinase C / physiology
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Rats
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin / chemistry
  • Receptors, Angiotensin / genetics
  • Receptors, Angiotensin / metabolism*
  • Signal Transduction
  • Time Factors
  • Transcriptional Activation
  • Transfection


  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin
  • Concanavalin A
  • Angiotensin II
  • ErbB Receptors
  • Proto-Oncogene Proteins pp60(c-src)
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Calcium