G-protein signaling - N-RAS regulation pathway

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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:

  1. Wolfman JC, Palmby T, Der CJ, Wolfman A
    Cellular N-Ras promotes cell survival by downregulation of Jun N-terminal protein kinase and p38. Molecular and cellular biology 2002 Mar;22(5):1589-606
  2. Takahashi C, Bronson RT, Socolovsky M, Contreras B, Lee KY, Jacks T, Noda M, Kucherlapati R, Ewen ME
    Rb and N-ras function together to control differentiation in the mouse. Molecular and cellular biology 2003 Aug;23(15):5256-68
  3. Zheng Y, Quilliam LA
    Activation of the Ras superfamily of small GTPases. Workshop on exchange factors. EMBO reports 2003 May;4(5):463-8
  4. 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
  5. 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
  6. Matallanas D, Arozarena I, Berciano MT, Aaronson DS, Pellicer A, Lafarga M, Crespo P
    Differences on the inhibitory specificities of H-Ras, K-Ras, and N-Ras (N17) dominant negative mutants are related to their membrane microlocalization. The Journal of biological chemistry 2003 Feb 14;278(7):4572-81
  7. 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
  8. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  9. Perez de Castro I, Bivona TG, Philips MR, Pellicer A
    Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus. Molecular and cellular biology 2004 Apr;24(8):3485-96
  10. 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
  11. Cullen PJ, Lockyer PJ
    Integration of calcium and Ras signalling. Nature reviews. Molecular cell biology 2002 May;3(5):339-48
  12. Omerovic J, Laude AJ, Prior IA
    Ras proteins: paradigms for compartmentalised and isoform-specific signalling. Cellular and molecular life sciences : CMLS 2007 Oct;64(19-20):2575-89
  13. Downward J
    Targeting RAS signalling pathways in cancer therapy. Nature reviews. Cancer 2003 Jan;3(1):11-22
  14. Maurer-Stroh S, Washietl S, Eisenhaber F
    Protein prenyltransferases. Genome biology 2003;4(4):212
  15. 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
  16. Hamilton M, Wolfman A
    Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo. Oncogene 1998 Mar;16(11):1417-28
  17. 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
  18. Kolch W
    Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. The Biochemical journal 2000 Oct 15;351 Pt 2:289-305
  19. Spaargaren M, Bischoff JR
    Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proceedings of the National Academy of Sciences of the United States of America 1994 Dec 20;91(26):12609-13
  20. 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

  1. Wolfman JC, Palmby T, Der CJ, Wolfman A
    Cellular N-Ras promotes cell survival by downregulation of Jun N-terminal protein kinase and p38. Molecular and cellular biology 2002 Mar;22(5):1589-606
  2. Takahashi C, Bronson RT, Socolovsky M, Contreras B, Lee KY, Jacks T, Noda M, Kucherlapati R, Ewen ME
    Rb and N-ras function together to control differentiation in the mouse. Molecular and cellular biology 2003 Aug;23(15):5256-68
  3. Zheng Y, Quilliam LA
    Activation of the Ras superfamily of small GTPases. Workshop on exchange factors. EMBO reports 2003 May;4(5):463-8
  4. 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
  5. 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
  6. Matallanas D, Arozarena I, Berciano MT, Aaronson DS, Pellicer A, Lafarga M, Crespo P
    Differences on the inhibitory specificities of H-Ras, K-Ras, and N-Ras (N17) dominant negative mutants are related to their membrane microlocalization. The Journal of biological chemistry 2003 Feb 14;278(7):4572-81
  7. 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
  8. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  9. Perez de Castro I, Bivona TG, Philips MR, Pellicer A
    Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus. Molecular and cellular biology 2004 Apr;24(8):3485-96
  10. 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
  11. Cullen PJ, Lockyer PJ
    Integration of calcium and Ras signalling. Nature reviews. Molecular cell biology 2002 May;3(5):339-48
  12. Omerovic J, Laude AJ, Prior IA
    Ras proteins: paradigms for compartmentalised and isoform-specific signalling. Cellular and molecular life sciences : CMLS 2007 Oct;64(19-20):2575-89
  13. Downward J
    Targeting RAS signalling pathways in cancer therapy. Nature reviews. Cancer 2003 Jan;3(1):11-22
  14. Maurer-Stroh S, Washietl S, Eisenhaber F
    Protein prenyltransferases. Genome biology 2003;4(4):212
  15. 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
  16. Hamilton M, Wolfman A
    Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo. Oncogene 1998 Mar;16(11):1417-28
  17. 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
  18. Kolch W
    Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. The Biochemical journal 2000 Oct 15;351 Pt 2:289-305
  19. Spaargaren M, Bischoff JR
    Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proceedings of the National Academy of Sciences of the United States of America 1994 Dec 20;91(26):12609-13
  20. 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

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