G-protein signaling - K-RAS regulation pathway

K-RAS regulation pathway

V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) belongs to Ras family of small GTPases and serves as a signal transducer from growth factor receptors and activates numerous effector molecules resulting in cell growth, differentiation and apoptosis [1], [2].

Guanine nucleotide exchange factors (GEFs) are essential for K-RAS activation [2]. Main GEFs for K-RAS are RAS guanyl releasing proteins 1 and 2 (CALDAG-GEFII, CALDAG-GEFI) [3], [4], Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1), which is activated by Lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation [5], and RAP1 GTP-GDP dissociation stimulator 1 (Rap1GDS1), which is stimulated by Kinesin-associated protein 3 (KAP3) binding [6].

K-RAS activation can be induced by Erythropoietin (Epo) and Epidermal growth factor (EGF) signaling [7], [8]. Activated Erythropoietin receptor (Epo receptor) and Epidermal growth factor receptor (EGFR) associate with SHC (Src homology 2 domain containing) transforming protein 1 (Shc), which binds to Growth factor receptor-bound protein 2 (GRB2) and this leads to Son of sevenless homolog (SOS) activation [9], [10], [11]. SOS promotes GTP loading on K-RAS and its activation [4].

K-RAS undergoes several posttranslational modifications that are essential for its proper plasma membrane localization. K-RAS modifications are also necessary for the biological function of the modified protein. Isoprenylcysteine carboxyl methyltransferase (ICMT) promotes carboxyl methylation of K-Ras and farnesyltransferase, CAAX box (FTase) catalyzes K-RAS farnesylation [12], [13], [14].

Subcellular localization and function of K-Ras are also modulated by Protein kinase C theta (PKC-theta)-mediated phosphorylation [15].

The best characterized K-Ras effectors are: the Raf kinase family that comprises 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 K-Ras activates the mitogen-activated protein kinase (MAPK) cascade [1], [2]; the Phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3K cat class IA (p110-alpha)) [16], and the family of RalGEFs that now includes Ral guanine nucleotide dissociation stimulator (RalGDS), Ral guanine nucleotide dissociation stimulator-like 1 and 2 (RGL1 and RGL2) [17]. Also, activated farnesylated K-RAS can form a complex with Ras association (RalGDS/AF-6) domain family member 1 (RASSF1) [18].

References:

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