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 .
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 , .
Like other G-proteins, H-Ras is found in two
interconvertible forms, GDP-bound inactive and GTP-bound active .
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
CALDAG-GEF II and CALDAG-GEF
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 .
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
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
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 , .
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
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 .
In addition, cytoplasmic Ca(2+) and second messenger
1,2-diacyl-glycerol (DAG) can activate calcium and
DAG-regulated GEFs (CALDAG-GEF II and
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) , , , .
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 , .
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