Cytoskeleton remodeling - RalB regulation pathway

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RalB regulation pathway

V-ral simian leukemia viral oncogene homolog B (RalB) is small GTPase. It belongs to the Ras superfamily of low molecular mass (20-30 kDa) GTP-binding proteins that influence cytoskeleton remodeling processes, endo- and exocytosis [1], [2], [3].

Activated v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) can modulate activity of RalB by recruiting Ral guanine nucleotide dissociation stimulator (RalGDS) that is shown to exhibit GEF activity towards RalB [4], [5], [6], [7].

Small GTPase Ras-like without CAAX 1 (RIT) can also activate RalB via binding to Ral guanine nucleotide dissociation stimulator-like 3 (RGL3) and stimulating its GEF activity [8].

In addition, Calmodulin binds to RalB in a Ca('2+)-dependent manner and activates it [9], [10].

Activated RalB directly binds to Exocyst complex component 2 (Sec5) and Exocyst complex component 8 (Exo84) and promotes assembly of exocyst complex and thus stimulates exocytosis [11], [12].

GTP-bound RalB binds to RalA binding protein 1 (RalBP1) and promotes activation of Cell division cycle 42 (CDC42) and Ras-related C3 botulinum toxin substrate 1 (RAC1) signaling pathways. In addition, RalB forms complexes with RalBP1, RALBP1 associated Eps domain containing 1 (REPS1) and RALBP1 associated Eps domain containing 2 (REPS2). This leads to stimulation of endocytosis [13], [14].

RalB is able to stimulate Phospholipase C delta 1 (PLC-delta 1) enzymatic activity independent of its guanine nucleotide status [15].

References:

  1. Hofer F, Berdeaux R, Martin GS
    Ras-independent activation of Ral by a Ca(2+)-dependent pathway. Current biology : CB 1998 Jul 2;8(14):839-42
  2. Camonis JH, White MA
    Ral GTPases: corrupting the exocyst in cancer cells. Trends in cell biology 2005 Jun;15(6):327-32
  3. Sugita S
    Mechanisms of exocytosis. Acta physiologica (Oxford, England) 2008 Feb;192(2):185-93
  4. Hofer F, Fields S, Schneider C, Martin GS
    Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proceedings of the National Academy of Sciences of the United States of America 1994 Nov 8;91(23):11089-93
  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. Kishida S, Koyama S, Matsubara K, Kishida M, Matsuura Y, Kikuchi A
    Colocalization of Ras and Ral on the membrane is required for Ras-dependent Ral activation through Ral GDP dissociation stimulator. Oncogene 1997 Dec 11;15(24):2899-907
  7. Matsubara K, Kishida S, Matsuura Y, Kitayama H, Noda M, Kikuchi A
    Plasma membrane recruitment of RalGDS is critical for Ras-dependent Ral activation. Oncogene 1999 Feb 11;18(6):1303-12
  8. Shao H, Andres DA
    A novel RalGEF-like protein, RGL3, as a candidate effector for rit and Ras. The Journal of biological chemistry 2000 Sep 1;275(35):26914-24
  9. 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
  10. Sidhu RS, Elsaraj SM, Grujic O, Bhullar RP
    Calmodulin binding to the small GTPase Ral requires isoprenylated Ral. Biochemical and biophysical research communications 2005 Oct 14;336(1):105-9
  11. Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA
    Ral GTPases regulate exocyst assembly through dual subunit interactions. The Journal of biological chemistry 2003 Dec 19;278(51):51743-8
  12. Rosse C, Hatzoglou A, Parrini MC, White MA, Chavrier P, Camonis J
    RalB mobilizes the exocyst to drive cell migration. Molecular and cellular biology 2006 Jan;26(2):727-34
  13. Yamaguchi A, Urano T, Goi T, Feig LA
    An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1. The Journal of biological chemistry 1997 Dec 12;272(50):31230-4
  14. Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A
    Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral. The Journal of biological chemistry 1998 Jan 9;273(2):814-21
  15. Sidhu RS, Clough RR, Bhullar RP
    Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin. The Journal of biological chemistry 2005 Jun 10;280(23):21933-41

  1. Hofer F, Berdeaux R, Martin GS
    Ras-independent activation of Ral by a Ca(2+)-dependent pathway. Current biology : CB 1998 Jul 2;8(14):839-42
  2. Camonis JH, White MA
    Ral GTPases: corrupting the exocyst in cancer cells. Trends in cell biology 2005 Jun;15(6):327-32
  3. Sugita S
    Mechanisms of exocytosis. Acta physiologica (Oxford, England) 2008 Feb;192(2):185-93
  4. Hofer F, Fields S, Schneider C, Martin GS
    Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proceedings of the National Academy of Sciences of the United States of America 1994 Nov 8;91(23):11089-93
  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. Kishida S, Koyama S, Matsubara K, Kishida M, Matsuura Y, Kikuchi A
    Colocalization of Ras and Ral on the membrane is required for Ras-dependent Ral activation through Ral GDP dissociation stimulator. Oncogene 1997 Dec 11;15(24):2899-907
  7. Matsubara K, Kishida S, Matsuura Y, Kitayama H, Noda M, Kikuchi A
    Plasma membrane recruitment of RalGDS is critical for Ras-dependent Ral activation. Oncogene 1999 Feb 11;18(6):1303-12
  8. Shao H, Andres DA
    A novel RalGEF-like protein, RGL3, as a candidate effector for rit and Ras. The Journal of biological chemistry 2000 Sep 1;275(35):26914-24
  9. 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
  10. Sidhu RS, Elsaraj SM, Grujic O, Bhullar RP
    Calmodulin binding to the small GTPase Ral requires isoprenylated Ral. Biochemical and biophysical research communications 2005 Oct 14;336(1):105-9
  11. Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA
    Ral GTPases regulate exocyst assembly through dual subunit interactions. The Journal of biological chemistry 2003 Dec 19;278(51):51743-8
  12. Rosse C, Hatzoglou A, Parrini MC, White MA, Chavrier P, Camonis J
    RalB mobilizes the exocyst to drive cell migration. Molecular and cellular biology 2006 Jan;26(2):727-34
  13. Yamaguchi A, Urano T, Goi T, Feig LA
    An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1. The Journal of biological chemistry 1997 Dec 12;272(50):31230-4
  14. Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A
    Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral. The Journal of biological chemistry 1998 Jan 9;273(2):814-21
  15. Sidhu RS, Clough RR, Bhullar RP
    Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin. The Journal of biological chemistry 2005 Jun 10;280(23):21933-41

Target Details

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