Development - Dopamine D2 receptor transactivation of EGFR

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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 D2 receptor class of dopamine receptors is a common target for most antipsychotics. Dopamine can also transactivate members of receptor tyrosine kinases family, such EGFR.

Dopamine D2 receptor transactivation of EGFR implicates c-Src via at least two mechanisms: direct phosphorylation of EGFR and/or phosphorylation of some matrix metalloproteinases (e.g. ADAM12) [1], [2], [3].

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

After EGFR phosphorylation, the receptor recruits adaptor proteins Shc and GRB2. In addition, Shc may be activated via Phosphoinositide-3-kinase. Activated Shc and GRB2 recruit SOS to the H-Ras. This results in rapid activation of H-Ras and subsequent activation of c-Raf-1/ MEK1(MAP2K1) and MEK2(MAP2K2), ERK2 (MAPK1) cascade [2], [3].

In addition, EGFR may activate PI3K cat class IA/ AKT(PKB) and thus, regulate cell negative regulation of neuron apoptosis [1].


Objects list:

ADAM12 Disintegrin and metalloproteinase domain-containing protein 12
AKT(PKB) AKT(PKB) Protein group
Dopamine Chemical IUPAC name 4-(2-Aminoethyl)benzene-1,2-diol
Dopamine D2 receptor D(2) dopamine receptor
EGFR Epidermal growth factor receptor
ERK1 (MAPK3) Mitogen-activated protein kinase 3
ERK2 (MAPK1) Mitogen-activated protein kinase 1
GRB2 Growth factor receptor-bound protein 2
H-Ras GTPase HRas
MEK1(MAP2K1) Dual specificity mitogen-activated protein kinase kinase 1
MEK2(MAP2K2) Dual specificity mitogen-activated protein kinase kinase 2
PI3K cat class IA The catalytic subunit of phosphatidylinositol 3-kinase subgroups IA Protein group
SOS SOS Protein group
Shc SHC-transforming protein 1
c-Raf-1 RAF proto-oncogene serine/threonine-protein kinase
c-Src Proto-oncogene tyrosine-protein kinase Src

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

  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

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