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:
- Takai Y, Sasaki T, Matozaki T
Small GTP-binding proteins.
Physiological reviews 2001 Jan;81(1):153-208
- 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
- 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
- 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
- Tallquist M, Kazlauskas A
PDGF signaling in cells and mice.
Cytokine & growth factor reviews 2004 Aug;15(4):205-13
- 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
- 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
- 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
- Matozaki T, Nakanishi H, Takai Y
Small G-protein networks: their crosstalk and signal cascades.
Cellular signalling 2000 Aug;12(8):515-24
- Paduch M, Jelen F, Otlewski J
Structure of small G proteins and their regulators.
Acta biochimica Polonica 2001;48(4):829-50
- 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
- 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