Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

G-protein signaling H-RAS regulation pathway

Log In to Post A Comment

G-protein signaling H-RAS regulation pathway

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 atarget of posttranslational modification via attachment of farnesyl or methyl lipidmoieties catalyzed by Farnesyltransferase ( FTase ) and Methyltransferase (ICMT ), respectively. These posttranslational modifications affect localizationand biological activity of H-Ras [2], [3].

Like other G-proteins, H-Ras is found in two interconvertible forms, GDP-boundinactive and GTP-bound active [1]. Conversion from GDP-bound form toGTP-bound is catalyzed by guanine nucleotide exchange factor (GEF). Activity of GEF isregulated 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, abinary complex of the small G protein and GEF is formed. Then GEF in this complex isreplaced 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 GTPaseactivity of H-Ras. Proteins known as GTPase activated proteins (GAP) have beenshown to stimulate this reaction. GAPs that inactivate H-Ras are p120GAPand 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 tyrosinekinase activity.

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

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

Other receptors, e.g., RET proto-oncogene ( RET ) and TEK tyrosine kinaseendothelial ( TIE2 ), can directly activate Docking proteins 1 and 2 ( DOK1and DOK2 ). DOK1 and DOK2 in turn stimulate the GAP activity ofp120GAP 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 andCALDAG-GEF III ).

Major effectors of H-Ras protein are protein kinase v-Raf-1 murine leukemiaviral oncogene homolog 1 ( c-Raf-1 ) and Phosphatidylinositol 3-kinase ( PI3Kcat class 1A ) [8], [9], [1], [10].

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