Pathway maps

Development_Dopamine D2 receptor transactivation of EGFR
Development_Dopamine D2 receptor transactivation of EGFR

Object List (links open in MetaCore):

GRB2, 2.7.1.137, MEK2(MAP2K2), EGFR, PDK (PDPK1), Dopamine D2 receptor, HB-EGF, MEK1(MAP2K1), PI3K cat class IA, ADAM12, PtdIns(3,4,5)P3, Shc, PI3K reg class IA, AKT, ERK2 (MAPK1), Dopamine extracellular region, G-protein alpha-i family, SOS, ERK1 (MAPK3), c-Src, c-Raf-1, G-protein beta/gamma, H-Ras, PtdIns(4,5)P2

Description

Dopamine D2 receptor transactivation of EGFR

Dopamine is a major transmitter and neuromodulator in the CNS. This transmitter mediates its signaling through GPCRs of which the Dopamine receptor D2 ( Dopamine D2 receptor ) class of dopamine receptors is a common target for most antipsychotics. Dopamine can also transactivate members of receptor tyrosine kinases family, such Epidermal growth factor receptor ( EGFR ).

Dopamine D2 receptor transactivation of EGFR implicates V-src sarcoma viral oncogene homolog ( c-Src ) via at least two mechanisms: direct phosphorylation of EGFR and/or phosphorylation of some matrix metalloproteinases (e.g. ADAM metallopeptidase domain 12 ( ADAM12 )) [1], [2], [3].

EGFR leads to distinct downstream signaling events, one of which is mediated by transactivation of EGFR via Mitogen-activated protein kinases 3 and 1 ( ERK1(MAPK3), ERK2(MAPK1) ) pathways [1], [4], [2].

After EGFR phosphorylation, the receptor recruits adaptor proteins Src homology 2 domain containing transforming protein ( Shc ) and Growth factor receptor bound 2 ( Grb2 ). In addition, Shc may be activated via Phosphoinositide-3-kinase ( PI3K ). Activated Shc and Grb2 recruit Son of sevenless proteins ( SOS ) to the small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ). This results in rapid activation of H-Ras and subsequent activation of V-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1(MAP2K1) and MEK2(MAP2K2) )/ ERK1(MAPK3), ERK2(MAPK1) cascade [2], [3].

In addition, EGFR may activate Phosphoinositide-3-kinase ( PI3K )/ V-akt murine thymoma viral oncogene homolog ( AKT(PKB) ) and thus, regulate cell survival during oxidative stress [1].

References:

  1. Nair VD, Sealfon SC
    Agonist-specific transactivation of phosphoinositide 3-kinase signaling pathway mediated by the dopamine D2 receptor. The Journal of biological chemistry 2003 Nov 21;278(47):47053-61
  2. Wang C, Buck DC, Yang R, Macey TA, Neve KA
    Dopamine D2 receptor stimulation of mitogen-activated protein kinases mediated by cell type-dependent transactivation of receptor tyrosine kinases. Journal of neurochemistry 2005 May;93(4):899-909
  3. Ohtsu H, Dempsey PJ, Eguchi S
    ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. American journal of physiology. Cell physiology 2006 Jul;291(1):C1-10
  4. Beom S, Cheong D, Torres G, Caron MG, Kim KM
    Comparative studies of molecular mechanisms of dopamine D2 and D3 receptors for the activation of extracellular signal-regulated kinase. The Journal of biological chemistry 2004 Jul 2;279(27):28304-14