G-protein signaling - H-RAS regulation pathway

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H-Ras signaling pathway

H-Ras belongs to a family of the small 20-40 kDa GTP-binding proteins (G-proteins) called monomeric G-proteins [1].

H-Ras is localized at the cytoplasmic surface of the plasma membrane. It is a target of posttranslational modification via attachment of farnesyl or methyl lipid moieties catalyzed by Farnesyltransferase (FTase) and Methyltransferase (ICMT), respectively. These posttranslational modifications affect localization and biological activity of H-Ras [2], [3].

Like other G-proteins, H-Ras is found in two interconvertible forms, GDP-bound inactive and GTP-bound active [1]. Conversion from GDP-bound form to GTP-bound is catalyzed by guanine nucleotide exchange factor (GEF). Activity of GEF is regulated by the upstream signals. GEFs that activate H-Ras are Son of Sevenless (SOS), PDZ-GEF1, CALDAG-GEF II and CALDAG-GEF III, RASGRF1, RASGRF2, and RasGRP4.

GEF first interacts with the GDP-bound form and releases bound GDP. As a result, a binary complex of the small G protein and GEF is formed. Then GEF in this complex is replaced by GTP resulting in formation of the GTP-bound small G protein [1].

Conversion of GTP-bound form to GDP-bound form is a result of slow intrinsic GTPase activity of H-Ras. Proteins known as GTPase activated proteins (GAP) have been shown to stimulate this reaction. GAPs that inactivate H-Ras are p120GAP and RASA3.

The activity of GEPs and GAPs is induced by a large variety of extracellular signals, most notably by those that activate receptors with intrinsic or associated tyrosine kinase activity.

The phosphotyrosines of the receptors, such as platelet-derived growth factor receptor beta (PDGF-R-beta), serve as docking sites for the adaptor proteins, such as Src homology 2 domain containing transforming protein (Shc). Shc forms an adaptor protein complex with Growth factor receptor bound 2 (GRB2). This protein complex recruits SOS, the most characterized H-Ras GEF, from the cytosol to produce a receptor-adaptor-GEF complex [4], [5].

G-protein-coupled receptors (GPCRs) can also activate H-Ras signaling. The Beta-1 adrenergic receptor binds to the PDZ-GEF1 leading to H-Ras activation [6].

Other receptors, e.g., RET proto-oncogene (RET) and TEK tyrosine kinase endothelial (TIE2), can directly activate Docking proteins 1 and 2 (DOK1 and DOK2). DOK1 and DOK2 in turn stimulate the GAP activity of p120GAP that down-regulate H-Ras signaling [7].

In addition, cytoplasmic Ca(2+) and second messenger 1,2-diacyl-glycerol (DAG) can activate calcium and DAG-regulated GEFs (CALDAG-GEF II and CALDAG-GEF III).

Major effectors of H-Ras protein are protein kinase v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) and Phosphatidylinositol 3-kinase (PI3K cat class 1A) [1], [8], [9], [10].

Small G-proteins are also known to cross-talk with each other. H-Ras activates guanine nucleotide exchange factors RalRGL and Tiam 1 that in turn activate small GTPases RalA and Rac1, respectively [11], [12].

References:

  1. Takai Y, Sasaki T, Matozaki T
    Small GTP-binding proteins. Physiological reviews 2001 Jan;81(1):153-208
  2. Hightower KE, Huang CC, Casey PJ, Fierke CA
    H-Ras peptide and protein substrates bind protein farnesyltransferase as an ionized thiolate. Biochemistry 1998 Nov 3;37(44):15555-62
  3. 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
  4. Kurokawa K, Kawai K, Hashimoto M, Ito Y, Takahashi M
    Cell signalling and gene expression mediated by RET tyrosine kinase. Journal of internal medicine 2003 Jun;253(6):627-33
  5. Tallquist M, Kazlauskas A
    PDGF signaling in cells and mice. Cytokine & growth factor reviews 2004 Aug;15(4):205-13
  6. Pak Y, Pham N, Rotin D
    Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation. Molecular and cellular biology 2002 Nov;22(22):7942-52
  7. Loughna S, Sato TN
    Angiopoietin and Tie signaling pathways in vascular development. Matrix biology : journal of the International Society for Matrix Biology 2001 Sep;20(5-6):319-25
  8. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J
    Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 1997 May 2;89(3):457-67
  9. Matozaki T, Nakanishi H, Takai Y
    Small G-protein networks: their crosstalk and signal cascades. Cellular signalling 2000 Aug;12(8):515-24
  10. Paduch M, Jelen F, Otlewski J
    Structure of small G proteins and their regulators. Acta biochimica Polonica 2001;48(4):829-50
  11. 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
  12. 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

  1. Takai Y, Sasaki T, Matozaki T
    Small GTP-binding proteins. Physiological reviews 2001 Jan;81(1):153-208
  2. Hightower KE, Huang CC, Casey PJ, Fierke CA
    H-Ras peptide and protein substrates bind protein farnesyltransferase as an ionized thiolate. Biochemistry 1998 Nov 3;37(44):15555-62
  3. 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
  4. Kurokawa K, Kawai K, Hashimoto M, Ito Y, Takahashi M
    Cell signalling and gene expression mediated by RET tyrosine kinase. Journal of internal medicine 2003 Jun;253(6):627-33
  5. Tallquist M, Kazlauskas A
    PDGF signaling in cells and mice. Cytokine & growth factor reviews 2004 Aug;15(4):205-13
  6. Pak Y, Pham N, Rotin D
    Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation. Molecular and cellular biology 2002 Nov;22(22):7942-52
  7. Loughna S, Sato TN
    Angiopoietin and Tie signaling pathways in vascular development. Matrix biology : journal of the International Society for Matrix Biology 2001 Sep;20(5-6):319-25
  8. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J
    Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 1997 May 2;89(3):457-67
  9. Matozaki T, Nakanishi H, Takai Y
    Small G-protein networks: their crosstalk and signal cascades. Cellular signalling 2000 Aug;12(8):515-24
  10. Paduch M, Jelen F, Otlewski J
    Structure of small G proteins and their regulators. Acta biochimica Polonica 2001;48(4):829-50
  11. 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
  12. 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

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