GET THE APP

Ras Signaling Pathway, Historical View
Journal of Cell Science & Therapy

Journal of Cell Science & Therapy
Open Access

ISSN: 2157-7013

+44 1300 500008

Editorial - (2014) Volume 5, Issue 4

Ras Signaling Pathway, Historical View

Fahad G B Alanazi1, Badi Q Alenazi1, Abdulaziz D Al- Faim1, Omar Bagadir1, Ali Al- Shangiti1, Omar Kujan2, Bassel Tarakji2, Saeed M Daboor2, Mohamed W Al- Rabea3, Waleed Tamimi4, Dhaifallah Alenizi5, Entissar AlSuhaibani6 and Faris Q Alenzi7*
1MOH, Riyadh, Saudi Arabia
2Al-Farabi Dental College, Riyadh, Saudi Arabia
3College of Medicine, King Abdulaziz Univ, Jeddah, KSA
4Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia
5College of Medicine, North Borders Univ., Arar, Saudi Arabia
6College of Science, KSU, Riyadh, Saudi Arabia
7College of Appl Med Sci., Salman bin Abdulaziz University, Al-Kharj, Saudi Arabia
*Corresponding Author: Faris Q Alenzi, College of Applied Medical Sciences, P.O.Box 422 Al-Kharj 11942, Saudi Arabia, Tel: 4693558 Email:

Abstract

It is increasingly clear that the three RAS genes, N-. H- and K-RAS, encode 21 kDa proteins which act as intracellular switches, play a signal transduction pathway in controlling cell growth and differentiation. The three genes are highly homologous, yet recent evidence suggests they may have distinct functions in different cell types and have a central role in many human diseases. This article reviews briefly the regulation of signaling mechanisms.

Background

The three major ras genes each encode 21 kDa proteins are localised to the cytoplasmic side of the plasma membrane [1] and act as intracellular switches in many of the signal transduction pathways that control cell growth and differentiation. The Ras proteins are members of the GTPase superfamily which share the property of cycling between active (GTP-bound) and inactive (GDP-bound) states [2,3].

Genomic structure and organisation of the three major RAS genes

The three Ras proteins are divided into 4 domains. There is 85% homology identity at their amino acids sequence. The human N-RAS gene is located on chromosome 1 (1 p22-p32) H-RAS on Chromosome 11 (11p15.1-p15.2) and K-RAS on Chromosome 12 (12p-12.1- pter) (O'Brien, 1984). There are also two human-RAS pseudogenes, H-RAS2 (on the X chromosome) and K-RAS (on chromosome 6). The three major Ras genes have a common structure consisting of four coding exons (numbered1-4) and a 5' non-coding exon (o) [4]. The K-RAS gene has two alternative fourth exons (exons 4A and 4B) encoding two isomorphic proteins [5]. Because the intron structures of the three genes vary greatly in size, there are marked differences in the size of these genes. Thus, the coding sequence of human N-RAS spans more than 7 kbp, H-RAS spans about 3 kbp and K-RAS more than 35 kbp [6]. H-RAS and N-RAS proteins each consist of 89 amino acids whereas K-RAS contains 188 amino acids [5].

Until recently, there was no clear evidence for function differences between biological activity of N-, H-, and K–RAS although their coding sequences are highly conserved [3]. Nevertheless, in many human malignancies there is a bias in favor of mutation of one of the three Ras genes [7]; while this may reflect the known tissue–specific difference expression of the different Ras isoforms or the action of different mutagens in different malignancies, it is also consistent with there being distinct functions of the three Ras proteins. In support of this, recent work from our laboratory has clearly indicated that H-RAS is more transforming than both N- and K-RAS in fibroblasts, while, N-RAS is more transforming in haemopoietic cells.

RAS activation

In quiescent cells of p21 Ras exists primarily in the inactive (GDP-bound) from. Upon activation to the GTP-bound state, p21 RAS can interact with a variety of effector molecules that transmit downstream signals [8-10].

Activation of normal Ras proteins is best understood for ligands (e.g., growth hormones and cytokines) which bind to receptor tyrosine kinase (RTKs) the cell surface (Satoh et al.,) [11]. Binding of ligand to RTKs leads to dimerization of these receptors and autophosphorylation selective thyrosins residue in cytoplasmic domain of the receptor [12]. These frequently act as binding sites for signalling molecules (such as adaptor protein) which contain SH2 domains, e.g., the growth factor receptor–bound protein 2 (GRB2) [13]. The SH3 domains of adaptor molecules then bind to a guanine nucleotide exchange factor (GEF) of which the best described is Son of sevenless (Sos) protein. The GRB2/Sos complex appears to be very important in Ras activation [14]. Indeed the principal function of GRB2 is thought to be recruitment of SOS to interact with Ras-GDP [15]. This reaction leads to the release of the GDP and the Ras protein then binds GTP to form Ras-GTP (active), which can then activate downstream effectors.

Normally the active (GTP-bound) state of Ras is transient due to its intrinsic GTPase activity which hydrolyses Ras-GTP to the inactive (Ras-GDP) state. However, the intrinsic GTP-ase activity of Ras protein is weak and insufficient under physiological conditions to maintain Ras in an inactive form. This regulatory activity of hydrolysis of Ras is strongly stimulated by a family of proteins known as GAP.

Signal transduction pathways involving Ras:

Raf-dependent pathway

The Raf proteins, which are serine/threonine kinases, are essential for Ras-induced proliferation and transformation [6,16]. Active Ras binds to Raf localizing it to the plasma membrane [17,18] where it can bind to and phosphorylate MEK mitogen activated protein kinase (MAPK) extracellular signal-related kinase (ERK)Kinase) [19,20]. MEK then phosphorylates and activates MAP kinase, another serine/threonine kinase, which ultimately activates transcription factors in the nucleus e.g. Fos, Jun and c-Myc [21,22] (Figure 1). This is a simplified scheme since Raf-MAP Kinase pathway is complex and many modifications have been described indifferent cell types (Figure 2).

cell-science-therapy-Signal-transduction

Figure 1: Signal transduction pathway involving Ras

cell-science-therapy-dependent-pathway

Figure 2: Raf dependent pathway

PI3K-dependent pathway

PI3K (phosphatidylmositol-3-OH kinase) has also been clearly demonstrated to be associated with Ras proteins and the ability of activated Ras to stimulate PI3K has been shown to be important in cellular transformation by Ras protein [23,24]. PI3K consists of 2 subunits: a catalytic (p110) and regulatory (p85) subunits (Carpenter and Cantley, 1990). Ras appears to act both upstream and downstream of PI3K. Evidence that Ras is upstream of PI3K came from the observation that Ras-GTP stably binds to the p110 sub-unit.

In conclusion, altered Ras pathway signaling may contribute to the development of several human cancers.

References

  1. Willingham MC, Pastan I, Shih TY, Scolnick EM (1980) Localization of the src gene product of the Harvey strain of MSV to plasma membrane of transformed cells by electron microscopic immunocytochemistry. Cell 19: 1005-1014.
  2. Kaziro Y, Itoh H, Kozasa T, Nakafuku M, Satoh T (1991) Structure and function of signal-transducing GTP-binding proteins. Annu Rev Bioch 60: 349-400.
  3. Capon DJ, Chen EY, Levinson AD, Seeburg PH, Goeddel DV (1983) Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature 302: 33-37.
  4. McGrath JP, Capon DJ, Smith DH, Chen EY, Seeburg PH, et al. (1983) Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature 304: 501-506.
  5. Lowy DR, Willumsen BM (1993) Function and regulation of ras. Annu Rev Biochem 62: 851-891.
  6. Toksoz D, Farr CJ, Marshall CJ (1989) Ras genes and acute myeloid leukaemia. Br J Haematol 71: 1-6.
  7. Field J, Broek D, Kataoka T, Wigler M (1987) Guanine nucleotide activation of, and competition between, RAS proteins from Saccharomyces cerevisiae. Mol Cell Biol 7: 2128-2133.
  8. Satoh T, Nakamura S, Kaziro Y (1987) Induction of neurite formation in PC12 cells by microinjection of proto-oncogenic Ha-ras protein preincubated with guanosine-5'-O-(3-thiotriphosphate). Mol Cell Biol 7: 4553-4556.
  9. Satoh T, Nakafuku M, Miyajima A, Kaziro Y (1991) Involvement of ras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4. ProcNatlAcadSci U S A 88: 3314-3318.
  10. Satoh T, Nakafuku M, Kaziro Y (1992) Function of Ras as a molecular switch in signal transduction. J BiolChem 267: 24149-24152.
  11. Aronheim A, Engelberg D, Li N, al-Alawi N, Schlessinger J, et al. (1994)Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway. Cell 78: 949-96.
  12. Okutani T, Okabayashi Y, Kido Y, Sugimoto Y, Sakaguchi K, et al. (1994) Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells. J BiolChem 269: 31310-31314.
  13. Buday L, Downward J (1993)Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73: 611-620.
  14. Byrne JL, Paterson HF, Marshall CJ (1996) p21Ras activation by the guanine nucleotide exchange factor Sos, requires the Sos/Grb2 interaction and a second ligand-dependent signal involving the Sos N-terminus. Oncogene 13: 2055-2065.
  15. Hall A (1994) A biochemical function for ras-at last. Science 264: 1413-1414.
  16. Schaap D, van der Wal J, Howe LR, Marshall CJ, van Blitterswijk WJ (1993) A dominant-negative mutant of raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21ras. J BiolChem 268: 20232-20236.
  17. MaraisR, LightY, PatersonHF, Marshall CJ(1995) Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 14: 3136-3145.
  18. Dent P, Haser W, Haystead TA, Vincent LA, Roberts TM, et al. (1992)Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science 257:1404-1407.
  19. Howe LR, Leevers SJ, Gómez N, Nakielny S, Cohen P, et al. (1992) Activation of the MAP kinase pathway by the protein kinase raf. Cell 71: 335-342.
  20. Marais R, Wynne J, Treisman R (1993) The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 73: 381-393.
  21. Cowley S, Paterson H, Kemp P, Marshall CJ (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77: 841-852.
  22. Sjölander A, Yamamoto K, Huber BE, Lapetina EG (1991) Association of p21ras with phosphatidylinositol 3-kinase. ProcNatlAcadSci U S A 88: 7908-7912.
  23. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, et al. (1997) Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89: 457-467.
Citation: Alanazi FGB, Alenazi BQ, Faim ADA, Bagadir O, Shangiti AA, et al. (2014) Ras Signaling Pathway, Historical View. J Cell Sci Ther 5:e117.

Copyright: © 2014 Alanazi FGB, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Top