G-protein signaling - N-RAS regulation pathway

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 [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 to Son 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 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 [4], [8], [9].

Other known GEF for N-RAS is RAS guanyl releasing protein 2 (CALDAG-GEFI) [7], [10]. These proteins can be activated by increased Ca(2'+) cytosol and DAG levels [11], [12] as well as by Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1) thet can be activated by Lck phosphorylation [10].

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 [13], [14], [15].

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 [16], [17], [18], 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) [19], [20].

References:

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