GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Could regulate the interactions of signaling molecules with the actin cytoskeleton. Promotes continuous elongation of cytoplasmic processes during cell motility and simultaneous retraction of the cell body changing the cell morphology.
Microphthalmia with linear skin defects (MLS) is an X-linked dominant, male-lethal syndrome characterized by microphthalmia, aplastic skin and agenesis of the corpus callosum, and is caused by the deletion of a 500 kb critical region in Xp22.3. Our laboratory isolated a novel rho GTPase-activating protein (rhoGAP) gene named ARHGAP6 from the MLS region. ARHGAP6 contains 14 exons encoding a 974 amino acid protein with three putative SH3-binding domains. Because exons 2-14 are deleted in all MLS patients, we hypothesized that ARHGAP6 may be responsible for some of the phenotypic features of MLS. We pursued two approaches to study the function of ARHGAP6 and its role in the pathogenesis of MLS: gene targeting of the rhoGAP domain in mouse embryonic stem cells and in vitro expression studies. Surprisingly, loss of the rhoGAP function of Arhgap6 does not cause any detectable phenotypic or behavioral abnormalities in the mutant mice. Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling.
Phospholipase C (PLC) and the small G protein RhoA are vital elements for the contraction of vascular smooth muscle cells. The available evidence points to altered PLC-delta1 activity as an element determining enhanced vascular tone in hypertension; however, the factor(s) responsible for increased PLC activity remains unknown. There is the data indicating that RhoA inhibits PLC-delta1 and factors downmodulating RhoA activate phospholipase. In the present study, we explore an impact of a newly identified human ARHGAP6 protein possessing GTPase stimulating activity for RhoA on the catalytic properties of PLC-delta1. Under in vitro conditions, ARHGAP6 protein activated PLC-delta1. ARHGAP6 protein bound PLC-delta1 and regulated its activity by masking the binding sites for inhibitory phospholipids. Moreover, ARHGAP6 increased the V(max) of PLC-delta1 and enhanced its response to Ca(2+) stimulation. A Western blot of immunoprecipitates from Cos-7 cells transfected with pcDNA3-ARHGAP6 and pcDNA3-PLCdelta1 showed the presence of ARHGAP6/PLC-delta1 complexes. The activity of PLC in cells overexpressing ARHGAP6 increased approximately 6-fold compared to control cells. The examination of ARHGAP6 expression in mononuclear cells isolated from the blood of patients with hypertension showed increased ARHGAP6 mRNA and protein levels compared to age-matched normotensive subjects. Enhanced expression of ARHGAP6 was associated with an elevated level of PLC activity and increased levels of IP(3) (1.6-fold) and DAG (2.3-fold). In summary, our data indicate that ARHGAP6 protein binds to and up regulates PLC-delta1 both under in vitro and in vivo conditions. Moreover, the elevated expression of ARHGAP6 provides possible explanation for the altered activity of PLC-delta1 in hypertension.
Phospholipase C (PLC) and the small G protein RhoA are vital elements for the contraction of vascular smooth muscle cells. The available evidence points to altered PLC-delta1 activity as an element determining enhanced vascular tone in hypertension; however, the factor(s) responsible for increased PLC activity remains unknown. There is the data indicating that RhoA inhibits PLC-delta1 and factors downmodulating RhoA activate phospholipase. In the present study, we explore an impact of a newly identified human ARHGAP6 protein possessing GTPase stimulating activity for RhoA on the catalytic properties of PLC-delta1. Under in vitro conditions, ARHGAP6 protein activated PLC-delta1. ARHGAP6 protein bound PLC-delta1 and regulated its activity by masking the binding sites for inhibitory phospholipids. Moreover, ARHGAP6 increased the V(max) of PLC-delta1 and enhanced its response to Ca(2+) stimulation. A Western blot of immunoprecipitates from Cos-7 cells transfected with pcDNA3-ARHGAP6 and pcDNA3-PLCdelta1 showed the presence of ARHGAP6/PLC-delta1 complexes. The activity of PLC in cells overexpressing ARHGAP6 increased approximately 6-fold compared to control cells. The examination of ARHGAP6 expression in mononuclear cells isolated from the blood of patients with hypertension showed increased ARHGAP6 mRNA and protein levels compared to age-matched normotensive subjects. Enhanced expression of ARHGAP6 was associated with an elevated level of PLC activity and increased levels of IP(3) (1.6-fold) and DAG (2.3-fold). In summary, our data indicate that ARHGAP6 protein binds to and up regulates PLC-delta1 both under in vitro and in vivo conditions. Moreover, the elevated expression of ARHGAP6 provides possible explanation for the altered activity of PLC-delta1 in hypertension.
Microphthalmia with linear skin defects (MLS) is an X-linked dominant, male-lethal syndrome characterized by microphthalmia, aplastic skin and agenesis of the corpus callosum, and is caused by the deletion of a 500 kb critical region in Xp22.3. Our laboratory isolated a novel rho GTPase-activating protein (rhoGAP) gene named ARHGAP6 from the MLS region. ARHGAP6 contains 14 exons encoding a 974 amino acid protein with three putative SH3-binding domains. Because exons 2-14 are deleted in all MLS patients, we hypothesized that ARHGAP6 may be responsible for some of the phenotypic features of MLS. We pursued two approaches to study the function of ARHGAP6 and its role in the pathogenesis of MLS: gene targeting of the rhoGAP domain in mouse embryonic stem cells and in vitro expression studies. Surprisingly, loss of the rhoGAP function of Arhgap6 does not cause any detectable phenotypic or behavioral abnormalities in the mutant mice. Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling.
Interacting selectively and non-covalently with a SH3 domain (Src homology 3) of a protein, small protein modules containing approximately 50 amino acid residues found in a great variety of intracellular or membrane-associated proteins.
Interacting selectively and non-covalently and simultaneously with one or more signal transduction molecules, usually acting as a scaffold to bring these molecules into close proximity either using their own SH2/SH3 domains (e.g. Grb2) or those of their target molecules (e.g. SAM68).
Proc. Natl. Acad. Sci. U.S.A. 93, 695-699 (1996)[PubMed:8570618]
An increasingly large number of proteins involved in signal transduction have been identified in recent years and shown to control different steps of cell survival, proliferation, and differentiation. Among the genes recently identified at the tip of the long arm of the human X chromosome, a novel gene, C1, encodes a protein that appears to represent a newly discovered member of the group of signaling proteins involved in regulation of the small GTP binding proteins of the ras superfamily. The protein encoded by C1, p115, is synthesized predominantly in cells of hematopoietic origin. It is characterized by two regions of similarity to motifs present in known proteins: GAP and SH3 homologous regions. Its localization in a narrow cytoplasmic region just below the plasma membrane and its inhibitory effect on stress fiber organization indicate that p115 may down regulate rho-like GTPases in hematopoietic cells.
Microphthalmia with linear skin defects (MLS) is an X-linked dominant, male-lethal syndrome characterized by microphthalmia, aplastic skin and agenesis of the corpus callosum, and is caused by the deletion of a 500 kb critical region in Xp22.3. Our laboratory isolated a novel rho GTPase-activating protein (rhoGAP) gene named ARHGAP6 from the MLS region. ARHGAP6 contains 14 exons encoding a 974 amino acid protein with three putative SH3-binding domains. Because exons 2-14 are deleted in all MLS patients, we hypothesized that ARHGAP6 may be responsible for some of the phenotypic features of MLS. We pursued two approaches to study the function of ARHGAP6 and its role in the pathogenesis of MLS: gene targeting of the rhoGAP domain in mouse embryonic stem cells and in vitro expression studies. Surprisingly, loss of the rhoGAP function of Arhgap6 does not cause any detectable phenotypic or behavioral abnormalities in the mutant mice. Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling.
The initiation of the activity of the inactive enzyme phospolipase C as the result of a series of molecular signals generated as a consequence of a G-protein coupled receptor binding to its physiological ligand.
Phospholipase C (PLC) and the small G protein RhoA are vital elements for the contraction of vascular smooth muscle cells. The available evidence points to altered PLC-delta1 activity as an element determining enhanced vascular tone in hypertension; however, the factor(s) responsible for increased PLC activity remains unknown. There is the data indicating that RhoA inhibits PLC-delta1 and factors downmodulating RhoA activate phospholipase. In the present study, we explore an impact of a newly identified human ARHGAP6 protein possessing GTPase stimulating activity for RhoA on the catalytic properties of PLC-delta1. Under in vitro conditions, ARHGAP6 protein activated PLC-delta1. ARHGAP6 protein bound PLC-delta1 and regulated its activity by masking the binding sites for inhibitory phospholipids. Moreover, ARHGAP6 increased the V(max) of PLC-delta1 and enhanced its response to Ca(2+) stimulation. A Western blot of immunoprecipitates from Cos-7 cells transfected with pcDNA3-ARHGAP6 and pcDNA3-PLCdelta1 showed the presence of ARHGAP6/PLC-delta1 complexes. The activity of PLC in cells overexpressing ARHGAP6 increased approximately 6-fold compared to control cells. The examination of ARHGAP6 expression in mononuclear cells isolated from the blood of patients with hypertension showed increased ARHGAP6 mRNA and protein levels compared to age-matched normotensive subjects. Enhanced expression of ARHGAP6 was associated with an elevated level of PLC activity and increased levels of IP(3) (1.6-fold) and DAG (2.3-fold). In summary, our data indicate that ARHGAP6 protein binds to and up regulates PLC-delta1 both under in vitro and in vivo conditions. Moreover, the elevated expression of ARHGAP6 provides possible explanation for the altered activity of PLC-delta1 in hypertension.
The aggregation and bonding together of a set of components to form a focal adhesion, a complex of intracellular signaling and structural proteins that provides a structural link between the internal actin cytoskeleton and the ECM, and also function as a locus of signal transduction activity.
Any process that stops, prevents, or reduces the frequency, rate or extent of focal adhesion assembly, the establishment and maturation of focal adhesions.
Microphthalmia with linear skin defects (MLS) is an X-linked dominant, male-lethal syndrome characterized by microphthalmia, aplastic skin and agenesis of the corpus callosum, and is caused by the deletion of a 500 kb critical region in Xp22.3. Our laboratory isolated a novel rho GTPase-activating protein (rhoGAP) gene named ARHGAP6 from the MLS region. ARHGAP6 contains 14 exons encoding a 974 amino acid protein with three putative SH3-binding domains. Because exons 2-14 are deleted in all MLS patients, we hypothesized that ARHGAP6 may be responsible for some of the phenotypic features of MLS. We pursued two approaches to study the function of ARHGAP6 and its role in the pathogenesis of MLS: gene targeting of the rhoGAP domain in mouse embryonic stem cells and in vitro expression studies. Surprisingly, loss of the rhoGAP function of Arhgap6 does not cause any detectable phenotypic or behavioral abnormalities in the mutant mice. Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling.
Any process that stops, prevents, or reduces the frequency, rate or extent of the assembly a stress fiber, a bundle of microfilaments and other proteins found in fibroblasts.
Microphthalmia with linear skin defects (MLS) is an X-linked dominant, male-lethal syndrome characterized by microphthalmia, aplastic skin and agenesis of the corpus callosum, and is caused by the deletion of a 500 kb critical region in Xp22.3. Our laboratory isolated a novel rho GTPase-activating protein (rhoGAP) gene named ARHGAP6 from the MLS region. ARHGAP6 contains 14 exons encoding a 974 amino acid protein with three putative SH3-binding domains. Because exons 2-14 are deleted in all MLS patients, we hypothesized that ARHGAP6 may be responsible for some of the phenotypic features of MLS. We pursued two approaches to study the function of ARHGAP6 and its role in the pathogenesis of MLS: gene targeting of the rhoGAP domain in mouse embryonic stem cells and in vitro expression studies. Surprisingly, loss of the rhoGAP function of Arhgap6 does not cause any detectable phenotypic or behavioral abnormalities in the mutant mice. Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling.
Phospholipase C (PLC) and the small G protein RhoA are vital elements for the contraction of vascular smooth muscle cells. The available evidence points to altered PLC-delta1 activity as an element determining enhanced vascular tone in hypertension; however, the factor(s) responsible for increased PLC activity remains unknown. There is the data indicating that RhoA inhibits PLC-delta1 and factors downmodulating RhoA activate phospholipase. In the present study, we explore an impact of a newly identified human ARHGAP6 protein possessing GTPase stimulating activity for RhoA on the catalytic properties of PLC-delta1. Under in vitro conditions, ARHGAP6 protein activated PLC-delta1. ARHGAP6 protein bound PLC-delta1 and regulated its activity by masking the binding sites for inhibitory phospholipids. Moreover, ARHGAP6 increased the V(max) of PLC-delta1 and enhanced its response to Ca(2+) stimulation. A Western blot of immunoprecipitates from Cos-7 cells transfected with pcDNA3-ARHGAP6 and pcDNA3-PLCdelta1 showed the presence of ARHGAP6/PLC-delta1 complexes. The activity of PLC in cells overexpressing ARHGAP6 increased approximately 6-fold compared to control cells. The examination of ARHGAP6 expression in mononuclear cells isolated from the blood of patients with hypertension showed increased ARHGAP6 mRNA and protein levels compared to age-matched normotensive subjects. Enhanced expression of ARHGAP6 was associated with an elevated level of PLC activity and increased levels of IP(3) (1.6-fold) and DAG (2.3-fold). In summary, our data indicate that ARHGAP6 protein binds to and up regulates PLC-delta1 both under in vitro and in vivo conditions. Moreover, the elevated expression of ARHGAP6 provides possible explanation for the altered activity of PLC-delta1 in hypertension.
Microphthalmia with linear skin defects (MLS) is an X-linked dominant, male-lethal syndrome characterized by microphthalmia, aplastic skin and agenesis of the corpus callosum, and is caused by the deletion of a 500 kb critical region in Xp22.3. Our laboratory isolated a novel rho GTPase-activating protein (rhoGAP) gene named ARHGAP6 from the MLS region. ARHGAP6 contains 14 exons encoding a 974 amino acid protein with three putative SH3-binding domains. Because exons 2-14 are deleted in all MLS patients, we hypothesized that ARHGAP6 may be responsible for some of the phenotypic features of MLS. We pursued two approaches to study the function of ARHGAP6 and its role in the pathogenesis of MLS: gene targeting of the rhoGAP domain in mouse embryonic stem cells and in vitro expression studies. Surprisingly, loss of the rhoGAP function of Arhgap6 does not cause any detectable phenotypic or behavioral abnormalities in the mutant mice. Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling.
Microphthalmia with linear skin defects (MLS) is an X-linked dominant, male-lethal syndrome characterized by microphthalmia, aplastic skin and agenesis of the corpus callosum, and is caused by the deletion of a 500 kb critical region in Xp22.3. Our laboratory isolated a novel rho GTPase-activating protein (rhoGAP) gene named ARHGAP6 from the MLS region. ARHGAP6 contains 14 exons encoding a 974 amino acid protein with three putative SH3-binding domains. Because exons 2-14 are deleted in all MLS patients, we hypothesized that ARHGAP6 may be responsible for some of the phenotypic features of MLS. We pursued two approaches to study the function of ARHGAP6 and its role in the pathogenesis of MLS: gene targeting of the rhoGAP domain in mouse embryonic stem cells and in vitro expression studies. Surprisingly, loss of the rhoGAP function of Arhgap6 does not cause any detectable phenotypic or behavioral abnormalities in the mutant mice. Transfected mammalian cells expressing ARHGAP6 lose their actin stress fibers, retract from the growth surface and extend thin, branching processes resembling filopodia. The ARHGAP6 protein co-localizes with actin filaments through an N-terminal domain and recruits F-actin into the growing processes. Mutation of a conserved arginine residue in the rhoGAP domain prevents the loss of stress fibers but has little effect on process outgrowth. These results suggest that ARHGAP6 has two independent functions: one as a GAP with specificity for RhoA and the other as a cytoskeletal protein that promotes actin remodeling.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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