Cytoskeleton remodeling - RalA regulation pathway

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RalA regulation pathway

v-Ral simian leukemia viral oncogene homolog A (RalA) belongs to a family of small GTP-binding proteins (G-proteins) called monomeric G-proteins. The Ral subfamily consists of RalA and RalB proteins.

RalA is localized at the cytoplasmic surface of the plasma membrane. It is a target of posttranslational modification via attachment of lipid moieties, such as geranyl, catalyzed by Geranylgeranyltransferase type I (GGTase-I). These posttranslational modifications affect localization and biological activity of RalA [1].

Like other G-proteins, RalA is found in two interconvertible forms, GDP-bound inactive and GTP-bound active. Conversion from the GDP- to GTP-bound form is catalyzed by Guanine nucleotide exchange factors (GEFs). Activity of GEF is often regulated by an upstream signal. GEF first interacts with the GDP-bound form and releases bound GDP. As a result, a binary complex of a small G protein and GEF is formed. GEF in this complex is subsequently replaced by GTP resulting in formation of the GTP-bound small G protein [2].

Three GEFs are known to interact with RalA. These are RalGDS, RGL, and RalGEF2. Two of them, RalGDS and RGL, have been found to be v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS) protein effectors [3], [4]. They also bind RAP1A member of RAS oncogene family (RAP-1A), but biological role of these interactions is unclear [4], [5].

RalGDS activity is affected by Formyl-Met-Leu-Phe receptor (FPR). RalGDS is localized to the cytosol and remains inactive in a complex formed with Beta-arrestins (Beta-arrestin 1 and Beta-arrestin 2). In response to FPR stimulation, Beta-arrestin/ RallGDS protein complexes dissociate, and RalGDS translocates with Beta-arrestin from the cytosol to the plasma membrane. This leads to activation of the RalA effector pathway that affects cytoskeletal rearrangements [6].

Conversion from GTP-bound form to GDP-bound form is a result of intrinsic GTPase activity of RalA. This activity is slow, and proteins called GTPase activated proteins (GAPs) are known to stimulate it. The GAP proteins for RalA were characterized and partially purified. However, their genes have not been cloned yet [2].

Aurora kinase (Aurora-A) phosphorylates and activites RalA [7]. Ral GTPases may also be involved in calcium/calmodulin-mediated intracellular signaling pathways where RalA is activated by Ca(2+) via binding with Calmodulin [8].

Effectors for RalA RalBP1, Phospholipase D 1 (PLD1), Filamin, and components of the exocyst implicate participation RalA in various cell processes.

RalBP1 contains a RhoGAP homology domain that exhibits the GAP activity for Ras-related C3 botulinum toxin substrate 1 (Rac1) and Cell division cycle 42 (CDC42) proteins, thereby inhibiting Rac1/CDC42 involved in cytoskeleton remodeling [9]. On the other hand, actin-binding protein Filamin is an effector protein of RalA. Filamin crosslinks Actin filaments into orthogonal networks and participates in the anchoring of membrane proteins to the Actin cytoskeleton [10].

RalA via RalBP1 interacts with the Mu-subunit of the heterotetrameric Coat assembly protein complex 2 (AP complex 2 medium (mu) chain) and RALBP1 associated Eps domain containing 1 and 2 (REPS1 and REPS2) proteins. These proteins are involved in endocytosis and cell motility [11], [12], [13].

Exocyst components Sec6, Sec6, Sec15B are direct effectors of RalA [14], [15], [16].

RalBP1 also interacts with the stress-responsive Heat shock factor 1 (HSF1) and regulates its activity [17].

Another RalA protein effector, PLD1, is implicated in vesicle trafficking. PLD1 directly associates with RalA. However, RalA has no effect on the activity of the PLD1. RalA is required for the stimulation of PLD1 activity by the ADP-ribosylation factor 1 (ARF1) [18].

Thus the RalA signaling appears to regulate vesicle trafficking, cytoskeleton organization, gene expression, and cell transformation.

References:

  1. Hinoi T, Kishida S, Koyama S, Ikeda M, Matsuura Y, Kikuchi A
    Post-translational modifications of Ras and Ral are important for the action of Ral GDP dissociation stimulator. The Journal of biological chemistry 1996 Aug 16;271(33):19710-6
  2. Takai Y, Sasaki T, Matozaki T
    Small GTP-binding proteins. Physiological reviews 2001 Jan;81(1):153-208
  3. Huang L, Hofer F, Martin GS, Kim SH
    Structural basis for the interaction of Ras with RalGDS. Nature structural biology 1998 Jun;5(6):422-6
  4. Peterson SN, Trabalzini L, Brtva TR, Fischer T, Altschuler DL, Martelli P, Lapetina EG, Der CJ, White GC 2nd
    Identification of a novel RalGDS-related protein as a candidate effector for Ras and Rap1. The Journal of biological chemistry 1996 Nov 22;271(47):29903-8
  5. 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
  6. Bhattacharya M, Anborgh PH, Babwah AV, Dale LB, Dobransky T, Benovic JL, Feldman RD, Verdi JM, Rylett RJ, Ferguson SS
    Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nature cell biology 2002 Aug;4(8):547-55
  7. Wu JC, Chen TY, Yu CT, Tsai SJ, Hsu JM, Tang MJ, Chou CK, Lin WJ, Yuan CJ, Huang CY
    Identification of V23RalA-Ser194 as a critical mediator for Aurora-A-induced cellular motility and transformation by small pool expression screening. The Journal of biological chemistry 2005 Mar 11;280(10):9013-22
  8. Clough RR, Sidhu RS, Bhullar RP
    Calmodulin binds RalA and RalB and is required for the thrombin-induced activation of Ral in human platelets. The Journal of biological chemistry 2002 Aug 9;277(32):28972-80
  9. 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
  10. Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP
    The small GTPase RalA targets filamin to induce filopodia. Proceedings of the National Academy of Sciences of the United States of America 1999 Mar 2;96(5):2122-8
  11. Oosterhoff JK, Penninkhof F, Brinkmann AO, Anton Grootegoed J, Blok LJ
    REPS2/POB1 is downregulated during human prostate cancer progression and inhibits growth factor signalling in prostate cancer cells. Oncogene 2003 May 15;22(19):2920-5
  12. Jullien-Flores V, Mahe Y, Mirey G, Leprince C, Meunier-Bisceuil B, Sorkin A, Camonis JH
    RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: involvement of the Ral pathway in receptor endocytosis. Journal of cell science 2000 Aug;113 ( Pt 16):2837-44
  13. Xu J, Zhou Z, Zeng L, Huang Y, Zhao W, Cheng C, Xu M, Xie Y, Mao Y
    Cloning, expression and characterization of a novel human REPS1 gene. Biochimica et biophysica acta 2001 Dec 3;1522(2):118-21
  14. Moskalenko S, Henry DO, Rosse C, Mirey G, Camonis JH, White MA
    The exocyst is a Ral effector complex. Nature cell biology 2002 Jan;4(1):66-72
  15. Polzin A, Shipitsin M, Goi T, Feig LA, Turner TJ
    Ral-GTPase influences the regulation of the readily releasable pool of synaptic vesicles. Molecular and cellular biology 2002 Mar;22(6):1714-22
  16. Brymora A, Valova VA, Larsen MR, Roufogalis BD, Robinson PJ
    The brain exocyst complex interacts with RalA in a GTP-dependent manner: identification of a novel mammalian Sec3 gene and a second Sec15 gene. The Journal of biological chemistry 2001 Aug 10;276(32):29792-7
  17. Hu Y, Mivechi NF
    HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo. The Journal of biological chemistry 2003 May 9;278(19):17299-306
  18. Luo JQ, Liu X, Frankel P, Rotunda T, Ramos M, Flom J, Jiang H, Feig LA, Morris AJ, Kahn RA, Foster DA
    Functional association between Arf and RalA in active phospholipase D complex. Proceedings of the National Academy of Sciences of the United States of America 1998 Mar 31;95(7):3632-7

  1. Hinoi T, Kishida S, Koyama S, Ikeda M, Matsuura Y, Kikuchi A
    Post-translational modifications of Ras and Ral are important for the action of Ral GDP dissociation stimulator. The Journal of biological chemistry 1996 Aug 16;271(33):19710-6
  2. Takai Y, Sasaki T, Matozaki T
    Small GTP-binding proteins. Physiological reviews 2001 Jan;81(1):153-208
  3. Huang L, Hofer F, Martin GS, Kim SH
    Structural basis for the interaction of Ras with RalGDS. Nature structural biology 1998 Jun;5(6):422-6
  4. Peterson SN, Trabalzini L, Brtva TR, Fischer T, Altschuler DL, Martelli P, Lapetina EG, Der CJ, White GC 2nd
    Identification of a novel RalGDS-related protein as a candidate effector for Ras and Rap1. The Journal of biological chemistry 1996 Nov 22;271(47):29903-8
  5. 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
  6. Bhattacharya M, Anborgh PH, Babwah AV, Dale LB, Dobransky T, Benovic JL, Feldman RD, Verdi JM, Rylett RJ, Ferguson SS
    Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nature cell biology 2002 Aug;4(8):547-55
  7. Wu JC, Chen TY, Yu CT, Tsai SJ, Hsu JM, Tang MJ, Chou CK, Lin WJ, Yuan CJ, Huang CY
    Identification of V23RalA-Ser194 as a critical mediator for Aurora-A-induced cellular motility and transformation by small pool expression screening. The Journal of biological chemistry 2005 Mar 11;280(10):9013-22
  8. Clough RR, Sidhu RS, Bhullar RP
    Calmodulin binds RalA and RalB and is required for the thrombin-induced activation of Ral in human platelets. The Journal of biological chemistry 2002 Aug 9;277(32):28972-80
  9. 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
  10. Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP
    The small GTPase RalA targets filamin to induce filopodia. Proceedings of the National Academy of Sciences of the United States of America 1999 Mar 2;96(5):2122-8
  11. Oosterhoff JK, Penninkhof F, Brinkmann AO, Anton Grootegoed J, Blok LJ
    REPS2/POB1 is downregulated during human prostate cancer progression and inhibits growth factor signalling in prostate cancer cells. Oncogene 2003 May 15;22(19):2920-5
  12. Jullien-Flores V, Mahe Y, Mirey G, Leprince C, Meunier-Bisceuil B, Sorkin A, Camonis JH
    RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: involvement of the Ral pathway in receptor endocytosis. Journal of cell science 2000 Aug;113 ( Pt 16):2837-44
  13. Xu J, Zhou Z, Zeng L, Huang Y, Zhao W, Cheng C, Xu M, Xie Y, Mao Y
    Cloning, expression and characterization of a novel human REPS1 gene. Biochimica et biophysica acta 2001 Dec 3;1522(2):118-21
  14. Moskalenko S, Henry DO, Rosse C, Mirey G, Camonis JH, White MA
    The exocyst is a Ral effector complex. Nature cell biology 2002 Jan;4(1):66-72
  15. Polzin A, Shipitsin M, Goi T, Feig LA, Turner TJ
    Ral-GTPase influences the regulation of the readily releasable pool of synaptic vesicles. Molecular and cellular biology 2002 Mar;22(6):1714-22
  16. Brymora A, Valova VA, Larsen MR, Roufogalis BD, Robinson PJ
    The brain exocyst complex interacts with RalA in a GTP-dependent manner: identification of a novel mammalian Sec3 gene and a second Sec15 gene. The Journal of biological chemistry 2001 Aug 10;276(32):29792-7
  17. Hu Y, Mivechi NF
    HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo. The Journal of biological chemistry 2003 May 9;278(19):17299-306
  18. Luo JQ, Liu X, Frankel P, Rotunda T, Ramos M, Flom J, Jiang H, Feig LA, Morris AJ, Kahn RA, Foster DA
    Functional association between Arf and RalA in active phospholipase D complex. Proceedings of the National Academy of Sciences of the United States of America 1998 Mar 31;95(7):3632-7

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