CD3 zeta, GRB2, SOS, PLC-gamma 1, ICMT, A-Raf-1, CD3, Ca('2+) endoplasmic reticulum lumen, Ca('2+) cytosol, B-Raf, Lck, CalDAG-GEFIII, PtdIns(4,5)P2, MHC class II, EGFR, DAG, TCR alpha/beta, RASGRF1, RalGDS, Shc, IP3 cytosol, ZAP70, CalDAG-GEFII, CD4, LAT, c-Raf-1, 18.104.22.168, <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), RGL1, N-Ras, IP3 receptor, CALDAG-GEFI, EGF, RGL2
N-RAS regulation pathway
Neuroblastoma RAS viral (v-ras) oncogene homolog ( N-RAS ) belongs to Ras family of small GTPases. It serves as a signal transducer from growth factor receptors and activates numerous effector molecules resulting in cell growth, differentiation and survival , . Guanine nucleotide exchange factors (GEFs) are essential for N-RAS activation .
N-RAS activation can be induced by Epidermal growth factor ( EGF ) signaling . 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 to Son of sevenless homolog ( SOS ) activation  . Activated SOS promotes GTP loading on N-RAS and its activation .
Ras activation is critical for T-cell development and function. Upon engagement of the T cell receptor ( TCR alpha/beta - CD3 complex ) by antigen presented on Major histocompatibility complex, class II ( MHC class II ) molecules, CD4 molecule ( CD4 )-bound Lymphocyte-specific protein tyrosine kinase ( Lck ) is activated and proceeds to phosphorylate CD247 molecule ( CD3 zeta ). This promotes the recruitment and subsequent activation of Zeta-chain (TCR) associated protein kinase 70kDa ( ZAP70 ). ZAP70 binds to Linker for activation of T cells ( LAT ) which recruits Phospholipase C gamma 1 ( PLC-gamma 1 ). Activated PLC-gamma 1 is responsible for the production of the second messenger 1,2-diacyl-glycerol ( DAG ). This activates RAS guanyl releasing protein 1 ( CALDAG-GEFII ), a known GEF for N-RAS , , .
Other known GEFs for N-RAS are RAS guanyl releasing proteins 2 and 3 ( CALDAG-GEFI, CALDAG-GEFIII ) , . These proteins can be activated by increased Ca(2'+) cytosol and DAG levels ,  as well as by Ras protein-specific guanine nucleotide-releasing factor 1 ( RASGRF1 ) thet can be activated by Lck phosphorylation .
N-RAS undergoes posttranslational modifications by Isoprenylcysteine carboxyl methyltransferase ( ICMT ) which promotes carboxyl methylation of N-Ras essential for its proper localization and cell function , , .
The best characterized N-Ras effectors are: the Raf kinase family comprised of v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ), v-raf murine sarcoma 3611 viral oncogene homolog ( A-Raf-1 ), and v-raf murine sarcoma viral oncogene homolog B1 ( B-Raf ), through which N-Ras activates the mitogen-activated protein kinase (MAPK) cascade , , , and a family of RalGEFs that now includes Ral guanine nucleotide dissociation stimulator ( RalGDS ), Ral guanine nucleotide dissociation stimulator-like 1 and 2 ( RGL1 and RGL2 ) , .