Angiotensin II stimulates ERK via two pathways in epithelial cells: protein kinase C suppresses a G-protein coupled receptor-EGF receptor transactivation pathway

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Abstract
In GN4 rat liver epithelial cells, angiotensin II (Ang II) produces intracellular calcium and protein kinase C (PKC) signals and stimulates ERK and JNK activity. JNK activation appears to be mediated by a calcium‐dependent tyrosine kinase (CADTK). To define the ERK pathway, we established GN4 cells expressing an inhibitory Ras(N17). Induction of Ras(N17) blocked EGF‐ but not Ang II‐ or phorbol ester (TPA)‐dependent ERK activation. In control cells, Ang II and TPA produced minimal increases in Ras–GTP level and Raf kinase activity. PKC depletion by chronic TPA exposure abolished TPA‐dependent ERK activation but failed to diminish the effect of Ang II. In PKC‐depleted cells, Ang II increased Ras–GTP level and activated Raf and ERK in a Ras‐dependent manner. In PKC depleted cells, Ang II stimulated Shc and Cbl tyrosine phosphorylation, suggesting that without PKC, Ang II activates another tyrosine kinase. PKC‐depletion did not alter Ang II‐dependent tyrosine phosphorylation or activity of p125FAK, CADTK, Fyn or Src, but PKC depletion or incubation with GF109203X resulted in Ang II‐dependent EGF receptor tyrosine phosphorylation. In PKC‐depleted cells, EGF receptor‐specific tyrosine kinase inhibitors blocked Ang II‐dependent EGF receptor and Cbl tyrosine phosphorylation, and ERK activation. In summary, Ang II can activate ERK via two pathways; the latent EGF receptor, Ras‐dependent pathway is equipotent to the Ras‐independent pathway, but is masked by PKC action. The prominence of this G‐protein coupled receptor to EGF receptor pathway may vary between cell types depending upon modifiers such as PKC.