G-protein signaling N-RAS regulation pathway
N-RAS regulation pathway
Neuroblastoma RAS viral (v-ras) oncogene homolog ( N-RAS ) belongs to Rasfamily of small GTPases. It serves as a signal transducer from growth factor receptorsand activates numerous effector molecules resulting in cell growth, differentiation andsurvival [1], [2]. Guanine nucleotide exchange factors (GEFs)are essential for N-RAS activation [3].
N-RAS activation can be induced by Epidermal growth factor ( EGF )signaling [4]. Activated Epidermal growth factor receptor ( EGFR )associates with SHC (Src homology 2 domain containing) transforming protein 1 (Shc ) and Growth factor receptor-bound protein 2 ( GRB2 ) and this leads toSon of sevenless homolog ( SOS ) activation [5] [6].Activated SOS promotes GTP loading on N-RAS and its activation [7].
Ras activation is critical for T-cell development and function. Upon engagement of theT cell receptor ( TCR alpha/beta - CD3 complex ) by antigen presented onMajor histocompatibility complex, class II ( MHC class II ) molecules, CD4molecule ( CD4 )-bound Lymphocyte-specific protein tyrosine kinase ( Lck )is activated and proceeds to phosphorylate CD247 molecule ( CD3 zeta ). Thispromotes the recruitment and subsequent activation of Zeta-chain (TCR) associated proteinkinase 70kDa ( ZAP70 ). ZAP70 binds to Linker for activation of T cells (LAT ) which recruits Phospholipase C gamma 1 ( PLC-gamma 1 ). ActivatedPLC-gamma 1 is responsible for the production of the second messenger1,2-diacyl-glycerol ( DAG ). This activates RAS guanyl releasing protein 1 (CALDAG-GEFII ), a known GEF for N-RAS [8], [9],[4].
Other known GEFs for N-RAS are RAS guanyl releasing proteins 2 and 3 (CALDAG-GEFI, CALDAG-GEFIII ) [10], [7]. Theseproteins can be activated by increased Ca(2'+) cytosol and DAG levels[11], [12] as well as by Ras protein-specific guaninenucleotide-releasing factor 1 ( RASGRF1 ) thet can be activated by Lckphosphorylation [10].
N-RAS undergoes posttranslational modifications by Isoprenylcysteine carboxylmethyltransferase ( ICMT ) which promotes carboxyl methylation of N-Rasessential for its proper localization and cell function [13], [14], [15].
The best characterized N-Ras effectors are: the Raf kinase family comprised ofv-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ), v-raf murine sarcoma3611 viral oncogene homolog ( A-Raf-1 ), and v-raf murine sarcoma viral oncogenehomolog B1 ( B-Raf ), through which N-Ras activates the mitogen-activatedprotein kinase (MAPK) cascade [16], [17], [18], and afamily of RalGEFs that now includes Ral guanine nucleotide dissociation stimulator (RalGDS ), Ral guanine nucleotide dissociation stimulator-like 1 and 2 (RGL1 and RGL2 ) [19], [20].
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