Pericyte‐specific expression of<i>Rgs5:</i>implications for PDGF and EDG receptor signaling during vascular maturation

Cho, Hyeseon; Kozasa, Tohru; Bondjers, Cecilia; Betsholtz, Christer; Kehrl, John H.

doi:10.1096/fj.02-0340fje

Cited by 183 publications

(176 citation statements)

References 26 publications

(31 reference statements)

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“…RGS5 and RGS16 Require GTPase Activation to Inhibit G qmediated Signaling-Consistent with previous reports showing that RGS5 and RGS16 can bind to G␣ q and accelerate its GTPase activity in vitro and modulate G q -mediated signaling in vivo (42)(43)(44), both RGS5 and RGS16 exerted an inhibitory effect on carbachol-induced PLC␤ activation in M 3 -expressing COS-7 cells (Fig. 3).…”

Section: Implications Of Expression Changes Of Key Components Of the supporting

confidence: 91%

“…As more mechanistic insights are gained, selective targeting of RGS subsets with similar regulatory mechanisms may become feasible. Additional questions raised by this study are (i) whether accelerated G protein inactivation is also a prerequisite for the inhibitory effect of RGS5 and RGS16 on G i/o signaling (22,42,44) and (ii) whether a similar differential behavior in RGS function can be found within members of other RGS families. …”

Section: Implications Of Expression Changes Of Key Components Of the mentioning

confidence: 98%

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Differential Contribution of GTPase Activation and Effector Antagonism to the Inhibitory Effect of RGS Proteins on Gq-mediated Signaling in Vivo

Anger

Zhang

Mende

2004

Journal of Biological Chemistry

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RGS proteins act as negative regulators of G protein signaling by serving as GTPase-activating proteins (GAP) for ␣ subunits of heterotrimeric G proteins (G␣), thereby accelerating G protein inactivation. RGS proteins can also block G␣-mediated signal production by competing with downstream effectors for G␣ binding. Little is known about the relative contribution of GAP and effector antagonism to the inhibitory effect of RGS proteins on G protein-mediated signaling. By comparing the inhibitory effect of RGS2, RGS3, RGS5, and RGS16 on G␣ q -mediated phospholipase C␤ (PLC␤) activation under conditions where GTPase activation is possible versus nonexistent, we demonstrate that members of the R4 RGS subfamily differ significantly in their dependence on GTPase acceleration. COS-7 cells were transiently transfected with either muscarinic M 3 receptors, which couple to endogenous G q protein and mediate a stimulatory effect of carbachol on PLC␤, or constitutively active G␣ q * , which is inert to GTP hydrolysis and activates PLC␤ independent of receptor activation. In M 3 -expressing cells, all of the RGS proteins significantly blunted the efficacy and potency of carbachol. In contrast, G␣ q * -induced PLC␤ activation was inhibited by RGS2 and RGS3 but not RGS5 and RGS16. The observed differential effects were not due to changes in M 3 , G␣ q / G␣ q * , PLC␤, or RGS expression, as shown by receptor binding assays and Western blots. We conclude that closely related R4 RGS family members differ in their mechanism of action. RGS5 and RGS16 appear to depend on G protein inactivation, whereas GAP-independent mechanisms (such as effector antagonism) are sufficient to mediate the inhibitory effect of RGS2 and RGS3.Many extracellular stimuli elicit intracellular responses by activating seven-transmembrane receptors that are coupled to heterotrimeric G proteins comprising ␣ and ␤␥ subunits (1, 2). The duration of the response of a cell to external signals is largely determined by the activation/inactivation cycle of G proteins. Activated receptors trigger GTP-for-GDP exchange on G␣ subunits, thus dissociating G␣ from G␤ ␥ and subsequent activation of downstream effectors (such as enzymes and ion channels). The duration of G protein activation is limited by GTPase activity intrinsic to G␣ subunits that catalyzes the conversion of active GTP-bound G␣ into inactive GDP-bound G␣, which in turn can reassociate with G␤␥ and receptors.RGS proteins belong to a family of more than 20 proteins with a conserved RGS core domain of ϳ120 amino acids that is necessary and sufficient for binding to G␣ subunits (3). They are divided into several subfamilies based on their structural similarities, gene organization, and function. RGS proteins act as regulators of G protein signaling by limiting the signals generated by G protein-coupled receptors. They markedly increase the rate at which G␣ subunits hydrolyze GTP to GDP, a property that defines them as GTPase-activating proteins (or GAPs) 1 (4). Hastening of G␣ inactivation facilitates the reass...

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Section: Implications Of Expression Changes Of Key Components Of the supporting

confidence: 91%

Section: Implications Of Expression Changes Of Key Components Of the mentioning

confidence: 98%

Differential Contribution of GTPase Activation and Effector Antagonism to the Inhibitory Effect of RGS Proteins on Gq-mediated Signaling in Vivo

Anger

Zhang

Mende

2004

Journal of Biological Chemistry

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“…32,33 Whether these or other pathways are regulated by RGS5 in pericytes in vivo remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Transcription Profiling of Platelet-Derived Growth Factor-B-Deficient Mouse Embryos Identifies RGS5 as a Novel Marker for Pericytes and Vascular Smooth Muscle Cells

Bondjers

Kalén²,

Hellström³

et al. 2003

The American Journal of Pathology

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213

163

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“…Regulator of G protein signaling-5 (RGS5), a potential negative regulator of Ras signaling, was up-regulated in the array and confirmed by qRT-PCR to be 3-fold elevated after Cremediated induction of K-ras V12 expression. This protein was originally identified in a screen for regulators of G protein signaling and has been shown to attenuate ERK activation in vivo (19,20).…”

Section: Up-regulation Of Negative Regulators Of Raf-mek-erk Signalingmentioning

confidence: 99%

Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K- ras oncogene in vivo

Sansom

Méniel²,

Wilkins³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

179

160

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Oncogenic mutations in the K-ras gene occur in Ϸ50% of human colorectal cancers. However, the precise role that K-ras oncogenes play in tumor formation is still unclear. To address this issue, we have conditionally expressed an oncogenic K-ras V12 allele in the small intestine of adult mice either alone or in the context of Apc deficiency. We found that expression of K-ras V12 does not affect normal intestinal homeostasis or the immediate phenotypes associated with Apc deficiency. Mechanistically we failed to find activation of the Raf͞MEK͞ERK pathway, which may be a consequence of the up-regulation of a number of negative feedback loops. However, K-ras V12 expression accelerates intestinal tumorigenesis and confers invasive properties after Apc loss over the long term. In renal epithelium, expression of the oncogenic Kras V12 allele in the absence of Apc induces the rapid development of renal carcinoma. These tumors, unlike those of intestinal origin, display activation of the Raf͞MEK͞ERK and Akt signaling pathways. Taken together, these data indicate that normal intestinal and kidney epithelium are resistant to malignant transformation by an endogenous K-ras oncogene. However, activation of K-ras V12 after Apc loss results in increased tumorigenesis with distinct kinetics. Whereas the effect of K-ras oncogenes in the intestine can been observed only after long latencies, they result in rapid carcinogenesis in the kidney epithelium. These data imply a window of opportunity for anti-K-ras therapies after tumor initiation in preventing tumor growth and invasion.colorectal cancer ͉ renal carcinoma ͉ Wnt signaling

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Pericyte‐specific expression ofRgs5:implications for PDGF and EDG receptor signaling during vascular maturation

Cited by 183 publications

References 26 publications

Differential Contribution of GTPase Activation and Effector Antagonism to the Inhibitory Effect of RGS Proteins on Gq-mediated Signaling in Vivo

Differential Contribution of GTPase Activation and Effector Antagonism to the Inhibitory Effect of RGS Proteins on Gq-mediated Signaling in Vivo

Transcription Profiling of Platelet-Derived Growth Factor-B-Deficient Mouse Embryos Identifies RGS5 as a Novel Marker for Pericytes and Vascular Smooth Muscle Cells

Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K- ras oncogene in vivo

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