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Development Dopamine D2 receptor transactivation of EGFR


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Development Dopamine D2 receptor transactivation of EGFR

Dopamine D2 receptor transactivation of EGFR

Dopamine is a major transmitter and neuromodulator in the CNS. This transmittermediates its signaling through GPCRs of which the Dopamine receptor D2 ( Dopamine D2receptor ) class of dopamine receptors is a common target for most antipsychotics.Dopamine can also transactivate members of receptor tyrosine kinases family, suchEpidermal growth factor receptor ( EGFR ).

Dopamine D2 receptor transactivation of EGFR implicates V-src sarcomaviral oncogene homolog ( c-Src ) via at least two mechanisms: directphosphorylation 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 bytransactivation 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 homology2 domain containing transforming protein ( Shc ) and Growth factor receptor bound2 ( 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 subsequentactivation of V-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/Mitogen-activated protein kinase kinase 1 and 2 ( MEK1(MAP2K1) andMEK2(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 cellsurvival during oxidative stress [1].