G-protein signaling K-RAS regulation pathway

K-RAS regulation pathway

V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( K-RAS ) belongs to Rasfamily of small GTPases and serves as a signal transducer from growth factor receptorsand activates numerous effector molecules resulting in cell growth, differentiation andapoptosis [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, 2 and 3( CALDAG-GEFII, CALDAG-GEFI, CALDAG-GEFIII ) [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 Epidermalgrowth factor ( EGF ) signaling [7], [8]. ActivatedErythropoietin receptor ( Epo receptor ) and Epidermal growth factor receptor (EGFR ) associate with SHC (Src homology 2 domain containing) transforming protein1 ( 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 andits activation [4].

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

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

The best characterized K-Ras effectors are: the Raf kinase family thatcomprises v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ), v-rafmurine sarcoma 3611 viral oncogene homolog ( A-Raf-1 ), and v-raf murine sarcomaviral oncogene homolog B1 ( B-Raf ), through which K-Ras activates themitogen-activated protein kinase (MAPK) cascade [1], [2]; thePhosphoinositide-3-kinase, catalytic, alpha polypeptide ( PI3K cat class IA(p110-alpha) ) [16], and the family of RalGEFs that now includes Ralguanine nucleotide dissociation stimulator ( RalGDS ), Ral guanine nucleotidedissociation 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].

1. Reuther GW, Der CJ
   The Ras branch of small GTPases: Ras family members don't fall far from the tree. Current opinion in cell biology 2000 Apr;12(2):157-65
2. Ellis CA, Clark G
   The importance of being K-Ras. Cellular signalling 2000 Jul;12(7):425-34
3. Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M
   Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. The Journal of biological chemistry 2000 Jun 30;275(26):20020-6
4. Ehrhardt A, Ehrhardt GR, Guo X, Schrader JW
   Ras and relatives--job sharing and networking keep an old family together. Experimental hematology 2002 Oct;30(10):1089-106
5. Giglione C, Gonfloni S, Parmeggiani A
   Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm. European journal of biochemistry / FEBS 2001 Jun;268(11):3275-83
6. Shimizu K, Kawabe H, Minami S, Honda T, Takaishi K, Shirataki H, Takai Y
   SMAP, an Smg GDS-associating protein having arm repeats and phosphorylated by Src tyrosine kinase. The Journal of biological chemistry 1996 Oct 25;271(43):27013-7
7. Ehrhardt A, David MD, Ehrhardt GR, Schrader JW
   Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen. Molecular and cellular biology 2004 Jul;24(14):6311-23
8. Zhang J, Lodish HF
   Identification of K-ras as the major regulator for cytokine-dependent Akt activation in erythroid progenitors in vivo. Proceedings of the National Academy of Sciences of the United States of America 2005 Oct 11;102(41):14605-10
9. Damen JE, Liu L, Cutler RL, Krystal G
   Erythropoietin stimulates the tyrosine phosphorylation of Shc and its association with Grb2 and a 145-Kd tyrosine phosphorylated protein. Blood 1993 Oct 15;82(8):2296-303
10. Carpenter G
    The EGF receptor: a nexus for trafficking and signaling. BioEssays : news and reviews in molecular, cellular and developmental biology 2000 Aug;22(8):697-707
11. Zhang J, Lodish HF
    Endogenous K-ras signaling in erythroid differentiation. Cell cycle (Georgetown, Tex.) 2007 Aug 15;6(16):1970-3
12. Long SB, Casey PJ, Beese LS
    The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 A resolution ternary complex structures. Structure (London, England : 1993) 2000 Feb 15;8(2):209-22
13. Maurer-Stroh S, Washietl S, Eisenhaber F
    Protein prenyltransferases. Genome biology 2003;4(4):212
14. Winter-Vann AM, Kamen BA, Bergo MO, Young SG, Melnyk S, James SJ, Casey PJ
    Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proceedings of the National Academy of Sciences of the United States of America 2003 May 27;100(11):6529-34
15. Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, Miura J, Wiener HH, Wright L, Saba SG, Yim D, Fein A, Perez de Castro I, Li C, Thompson CB, Cox AD, Philips MR
    PKC Regulates a Farnesyl-Electrostatic Switch on K-Ras that Promotes its Association with Bcl-Xl on Mitochondria and Induces Apoptosis. Molecular cell 2006 Feb 17;21(4):481-93
16. Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B, Nye E, Stamp G, Alitalo K, Downward J
    Binding of Ras to Phosphoinositide 3-Kinase p110alpha Is Required for Ras- Driven Tumorigenesis in Mice. Cell 2007 Jun 1;129(5):957-68
17. Rodriguez-Viciana P, Sabatier C, McCormick F
    Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Molecular and cellular biology 2004 Jun;24(11):4943-54
18. Donninger H, Vos MD, Clark GJ
    The RASSF1A tumor suppressor. Journal of cell science 2007 Sep 15;120(Pt 18):3163-72