G-protein signaling - Cross-talk between Ras-family GTPases

Cross-talk between Ras-family GTPases

GTPases of the Ras superfamily act as molecular switches to control a wide range of essential biochemical pathways in all eukaryotic cells. The members of this superfamily are structurally classified into at least five families: Ras, Rho, Rab, Sar1/Arf, and Ran [1]. Different members of Ras-family form signaling cascades that are involved in various cellular functions acting in a cooperative or antagonistic manner. Thus, Ras GTPases appear to exert their functions through their mutual crosstalk and multiple downstream effectors in a variety of cellular functions [1], [2].

Ras GTPases have two interconvertible forms: GDP-bound inactive and GTP-bound active forms. Guanine nucleotide exchange factors (GEFs) promote GTP loading essential for Ras GTPase activation. GTPase activating proteins (GAPs) stimulate hydrolysis of GTP to GDP which negatively regulates Ras protein activity [3].

GEFs and GAPs also can be downstream effectors of Ras proteins. RAS p21 protein activator 1 (p120GAP) modulates activity of v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) [4], and thus influences activation of H-Ras-induced Phosphoinositide-3-kinase, catalytic (PI3K cat class IA)/ V-Akt murine thymoma viral oncogene homolog (AKT(PKB)) signaling and stimulation of Ral guanine nucleotide dissociation stimulator (RalGDS) and T-cell lymphoma invasion and metastasis 1 (Tiam1). RalGDS and Tiam1, in turn, are GEFs for V-ral simian leukemia viral oncogene homolog A (RalA) and Ras-related C3 botulinum toxin substrate 1 (Rac1) [2], [5], [6], [7].

Another member of Ras family Muscle RAS oncogene homolog (M-RAS) regulated by p120GAP can modulate activity of Rap guanine nucleotide exchange factor 5 (MR-GEF). MR-GEF is a GEF for RAP1A member of RAS oncogene family (RAP-1A) [8]. In turn, RAP-1A binds to and inhibits p120GAP [9]. p120GAP negatively regulates activity of Rho GTPase activating protein 5 (RhoGAP5). RhoGAP5 is a common GAP for Rho subfamily members Rac1, Cell division cycle 42 (CDC42) and Ras homolog gene family, member A (RhoA) [10]. V-ral simian leukemia viral oncogene homolog A (RalA) also can influence Rac1 and CDC42 activity by regulation of their common GAP, RalA binding protein 1 (RalBP1) [11]. Activated Rac1 in turn can activate MCF.2 cell line derived transforming sequence-like (DBS), common activator for CDC42 and RhoA [12].

Ras family members can intersect its cellular function at the level of common downstream targets and cascades. Rac1, RhoA and RalA promote Phospholipase D1, phosphatidylcholine-specific (PLD1) activation [13]. H-Ras and RAP-1A common effectors are: the Raf kinase family members v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) and v-raf murine sarcoma viral oncogene homolog B1 (B-Raf). Thus H-Ras and RAP-1A promote MAPK cascade activation that is also common for Rac1 and CDC42 [2], [14], [15].

References:

1. Matozaki T, Nakanishi H, Takai Y
   Small G-protein networks: their crosstalk and signal cascades. Cellular signalling 2000 Aug;12(8):515-24
2. Bar-Sagi D, Hall A
   Ras and Rho GTPases: a family reunion. Cell 2000 Oct 13;103(2):227-38
3. 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
4. Giglione C, Parrini MC, Baouz S, Bernardi A, Parmeggiani A
   A new function of p120-GTPase-activating protein. Prevention of the guanine nucleotide exchange factor-stimulated nucleotide exchange on the active form of Ha-ras p21. The Journal of biological chemistry 1997 Oct 3;272(40):25128-34
5. Albright CF, Giddings BW, Liu J, Vito M, Weinberg RA
   Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase. The EMBO journal 1993 Jan;12(1):339-47
6. Katz ME, McCormick F
   Signal transduction from multiple Ras effectors. Current opinion in genetics & development 1997 Feb;7(1):75-9
7. Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG, Der CJ
   Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature cell biology 2002 Aug;4(8):621-5
8. Rebhun JF, Castro AF, Quilliam LA
   Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction. The Journal of biological chemistry 2000 Nov 10;275(45):34901-8
9. Frech M, John J, Pizon V, Chardin P, Tavitian A, Clark R, McCormick F, Wittinghofer A
   Inhibition of GTPase activating protein stimulation of Ras-p21 GTPase by the Krev-1 gene product. Science (New York, N.Y.) 1990 Jul 13;249(4965):169-71
10. Tatsis N, Lannigan DA, Macara IG
    The function of the p190 Rho GTPase-activating protein is controlled by its N-terminal GTP binding domain. The Journal of biological chemistry 1998 Dec 18;273(51):34631-8
11. Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH
    Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. The Journal of biological chemistry 1995 Sep 22;270(38):22473-7
12. Cheng L, Mahon GM, Kostenko EV, Whitehead IP
    Pleckstrin homology domain-mediated activation of the rho-specific guanine nucleotide exchange factor Dbs by Rac1. The Journal of biological chemistry 2004 Mar 26;279(13):12786-93
13. Bishop AL, Hall A
    Rho GTPases and their effector proteins. The Biochemical journal 2000 Jun 1;348 Pt 2:241-55
14. Olson MF, Ashworth A, Hall A
    An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science (New York, N.Y.) 1995 Sep 1;269(5228):1270-2
15. Lim L, Manser E, Leung T, Hall C
    Regulation of phosphorylation pathways by p21 GTPases. The p21 Ras-related Rho subfamily and its role in phosphorylation signalling pathways. European journal of biochemistry / FEBS 1996 Dec 1;242(2):171-85