Pathway maps

Development_Angiotensin activation of ERK
Development_Angiotensin activation of ERK

Object List (links open in MetaCore):, IP3, Ca('2+) endoplasmic reticulum lumen, ERK1 (MAPK3), GRB2, MEK2(MAP2K2), MEK1(MAP2K1), c-Src, PKC-delta, Angiotensin II receptor, type-1, PLC-beta, H-Ras, ADAM12, SOS, Ca('2) cytosol, c-Fos, Elk-1, DAG, Calmodulin, IP3 receptor, Angiotensin II, <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), ERK2 (MAPK1), CaMK II, G-protein beta/gamma, c-Raf-1, HB-EGF, PtdIns(4,5)P2, EGFR, G-protein alpha-q/11, Pyk2(FAK2), G-protein alpha-i family, Shc


Angiotensin's activation of ERK via transactivation of EGFR

Angiotensin II, a major effector peptide of the renin-angiotensin system, is believed to play a critical role in the pathogenesis of cardiovascular remodeling associated with hypertension, heart failure, and atherosclerosis. [1]

Angiotensin II receptor, type-1 mediates major cardiovascular effects of Angiotensin II. It belongs to the guanine nucleotide-binding regulatory protein (G protein)-coupled receptor (GPCR) superfamily. [2] Human Angiotensin II receptor, type-1 is found in liver, lung, adrenal, and adrenocortical adenomas [3].

In general terms, the mechanisms used by GPCRs to stimulate mitogen-activated protein kinases (MAPKs) fall into one of several broad categories. One of the important mechanisms involves the cross-talk between GPCRs and classical receptor tyrosine kinase, e.g., Epidermal growth factor receptor ( EGFR ). This process is called transactivation.

Upon binding with Angiotensin II the Angiotensin II receptor, type-1 is stabilized in its active conformation and stimulates heterotrimeric G proteins. In many Angiotensin II target cells, the Angiotensin II receptor, type-1 interacts primarily with Gq/11 proteins. However, the angiotensin II receptor, type-1 is also coupled with Gi proteins in hepatocytes [4], [5] and in adrenal, pituitary, and renal cells [6], [7]. These G-proteins dissociate into alpha ( G-protein alpha-q/11 and G-protein alpha-i family ) and beta/gamma ( G-protein beta/gamma ) subunits [8]. Both subunits take part in the activation of mitogen-activated protein kinase cascade.

G-protein alpha-q/11 and/or G-protein beta/gamma activate the v-Src sarcoma viral oncogene homolog ( c-Src ) [9]. In addition, G alpha and G beta/gamma subunits act as signal transducers for activation of the Phospholipase C beta ( PLC-beta ) [10]. PLC-beta activation leads to hydrolysis of Phosphatidylinositol 4,5-bisphosphate ( PtdIns(4,5)P2 ) and formation of Diacylglycerol ( DAG ) and Inositol trisphosphate ( IP3 ). DAG and IP3 stimulate the Protein kinase C, type delta ( PKC-delta ) and mobilize intracellular Ca2+, respectively [11].

Angiotensin II receptor, type-1 induces activation of Ca2+/ Calmodulin -dependent protein kinase II ( CaMK II ) and PKC-delta. Both kinases phosphorylate PTK2B protein tyrosine kinase 2 beta ( Pyk2(FAK2) ) and activate Pyk2(FAK2)/ c-Src kinase complex [12], [13], [7], [14].

Activated c-Src is a key intermediate in transactivation of the EGFR through metalloproteases (ADAMs, e.g. ADAM12 )/ Heparin-binding EGF-like growth factor ( HB-EGF ) pathway.

Like other members of the EGF family, HB-EGF is synthesized as a membrane-anchored insoluble form and then processed to a bioactive soluble form. This process is called ectodomain shedding [15].

HB-EGF activates EGFR and stimulates EGFR phosphorylation by c-Src [9].

After EGFR phosphorylation, this receptor recruits adaptor proteins (Src homology 2 domain containing transforming protein ( Shc ) and Growth factor receptor bound 2 ( GRB2 )) Then, these adaptor proteins are activated by Pyk2(FAK2) and c-Src [13], [9].

Activated Shc and GRB2 recruit Son of sevenless proteins ( SOS ) for the small GTPase H-Ras. This results in rapid activation of the H-Ras and subsequentl activation of the v-Raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ Mitogen-activated protein kinases 1 and 3 ( ERK2 and ERK1 ) kinase cascade [7].

Activation by Angiotensin II leads to nuclear translocation of the ERK1 and ERK2 and further to activation of certain transcription factors (e.g., c-Fos, Elk-1). Thus, ERK signaling cascade participates in a diversity of cellular functions [16].


  1. Goodfriend TL, Elliott ME, Catt KJ
    Angiotensin receptors and their antagonists. The New England journal of medicine 1996 Jun 20;334(25):1649-54
  2. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE
    Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature 1991 May 16;351(6323):233-6
  3. Takayanagi R, Ohnaka K, Sakai Y, Nakao R, Yanase T, Haji M, Inagami T, Furuta H, Gou DF, Nakamuta M
    Molecular cloning, sequence analysis and expression of a cDNA encoding human type-1 angiotensin II receptor. Biochemical and biophysical research communications 1992 Mar 16;183(2):910-6
  4. Pobiner BF, Northup JK, Bauer PH, Fraser ED, Garrison JC
    Inhibitory GTP-binding regulatory protein Gi3 can couple angiotensin II receptors to inhibition of adenylyl cyclase in hepatocytes. Molecular pharmacology 1991 Aug;40(2):156-67
  5. Tsygankova OM, Peng M, Maloney JA, Hopkins N, Williamson JR
    Angiotensin II induces diverse signal transduction pathways via both Gq and Gi proteins in liver epithelial cells. Journal of cellular biochemistry 1998 Apr 1;69(1):63-71
  6. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T
    International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacological reviews 2000 Sep;52(3):415-72
  7. Shah BH, Catt KJ
    Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: roles of protein kinase Cdelta, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation. Molecular pharmacology 2002 Feb;61(2):343-51
  8. Luttrell LM, Daaka Y, Lefkowitz RJ
    Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Current opinion in cell biology 1999 Apr;11(2):177-83
  9. Luttrell DK, Luttrell LM
    Not so strange bedfellows: G-protein-coupled receptors and Src family kinases. Oncogene 2004 Oct 18;23(48):7969-78
  10. Ushio-Fukai M, Griendling KK, Akers M, Lyons PR, Alexander RW
    Temporal dispersion of activation of phospholipase C-beta1 and -gamma isoforms by angiotensin II in vascular smooth muscle cells. Role of alphaq/11, alpha12, and beta gamma G protein subunits. The Journal of biological chemistry 1998 Jul 31;273(31):19772-7
  11. Thomas WG, Qian H, Smith NJ
    When 6 is 9: 'uncoupled' AT1 receptors turn signalling on its head. Cellular and molecular life sciences : CMLS 2004 Nov;61(21):2687-94
  12. Murasawa S, Mori Y, Nozawa Y, Gotoh N, Shibuya M, Masaki H, Maruyama K, Tsutsumi Y, Moriguchi Y, Shibazaki Y, Tanaka Y, Iwasaka T, Inada M, Matsubara H
    Angiotensin II type 1 receptor-induced extracellular signal-regulated protein kinase activation is mediated by Ca2+/calmodulin-dependent transactivation of epidermal growth factor receptor. Circulation research 1998 Jun 29;82(12):1338-48
  13. Eguchi S, Iwasaki H, Inagami T, Numaguchi K, Yamakawa T, Motley ED, Owada KM, Marumo F, Hirata Y
    Involvement of PYK2 in angiotensin II signaling of vascular smooth muscle cells. Hypertension 1999 Jan;33(1 Pt 2):201-6
  14. Ginnan R, Singer HA
    CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle. American journal of physiology. Cell physiology. 2002 Apr;282(4):C754-61
  15. Tanaka M, Nanba D, Mori S, Shiba F, Ishiguro H, Yoshino K, Matsuura N, Higashiyama S
    ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands. The Journal of biological chemistry 2004 Oct 1;279(40):41950-9
  16. Berk BC, Corson MA
    Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. Circulation research 1997 May;80(5):607-16