Phosphorylation of GTP dissociation inhibitor by PKA negatively regulates RhoA

Qiao, Jie; Holian, Oksana; Lee, Bao‐Shiang; Huang, Fei; Zhang, Jihang; Lum, Hazel

doi:10.1152/ajpcell.00139.2008

Cited by 54 publications

(44 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, Rho GTPases are involved in the development of pain memory by modulating dendritic spine morphology and density in the SCDH (20,21). Several studies have shown that the phosphorylation of GDI is capable of inducing the dissociation of GDI from Rho GTPase, resulting in the activation of Rho GTPase (22)(23)(24). In the present study, the phosphorylation level of GDI1 was not changed in the inflammatory pain model compared to the control, but EA treatment decreased the phosphorylation level.…”

Section: Discussioncontrasting

confidence: 47%

Phosphoproteomic analysis of electroacupuncture analgesia in an inflammatory pain rat model

Lee

Kim

et al. 2012

Mol Med Report

View full text Add to dashboard Cite

Abstract. The phosphorylation changes of nociceptive signaling proteins in the spinal cord dorsal horn (SCDH) are important in creating exaggerated pain following peripheral inflammation. Electroacupuncture (EA) has been widely used to relieve acute and chronic inflammatory pain in human and experimental pain models. In the present study, we performed a phosphoproteomic analysis to investigate whether EA alters protein phosphorylation in SCDH to attenuate pain development. Inflammatory hyperalgesia was induced by intraplantar injection of complete Freund's adjuvant (CFA) into the rat hind paw. EA treatment at ST36 and SP6 acupoints alleviated thermal hyperalgesia of the CFA-induced inflammatory pain model rats. The SCDH proteins from the control, inflammatory pain model and EA treatment rats were separated by 2-dimensional gel electrophoresis and the alterations in phosphoproteins were detected by Pro-Q Diamond staining. Eight proteins were differentially phosphorylated following EA treatment in the inflammatory pain model. Aldolase C, nascent polypeptide-associated complex α, stress-induced phosphoprotein 1 and heat shock protein 90 were identified as phosphoproteins whose expression was increased, whereas GDP dissociation inhibitor 1, thiamine triphosphatase, phosphoglycerate kinase 1 and 14-3-3 γ were phosphoproteins whose expression was decreased. This is the first phosphoproteomic screening study to elucidate the working mechanisms of EA analgesia. The results suggest that the regulation of cellular pathways in which the identified proteins are involved may be associated with an EA analgesic mechanism. IntroductionPeripheral inflammation frequently leads to the development of chronic pain, which is a leading cause of disability globally. In inflammatory pain, peripheral stimuli activate primary afferent neurons and are transmitted to secondary sensory neurons in the spinal cord dorsal horn (SCDH). Persistent noxious stimuli increase the excitability of secondary neurons in the SCDH and decrease the pain threshold. Early studies attributed this central sensitization to the facilitated synaptic transmission of nociceptive signals in the SCDH (1,2). Various signaling molecules such as glutamate receptors, protein kinase A (PKA), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), Ca 2+ -/calmodulin-dependent kinase II (CaMKII) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38 and c-jun N-terminal kinase (JNK), have been shown to be involved in altered nociceptive processing in the SCDH (3-5). Activation of these molecules is capable of inducing signaling cascades that lead to the subsequent expression of pain-associated genes such as prodynorphin, neurokinin-1 (NK-1) and cyclooxygenase-2 (COX-2) (6,7).Acupuncture, a traditional therapeutic method in oriental medicine, has long been clinically used to relieve pain. In particular, electroacupuncture (EA), where electrical stimulation is applied to acupuncture needles, is widely used in clinical an...

show abstract

Section: Discussioncontrasting

confidence: 47%

Phosphoproteomic analysis of electroacupuncture analgesia in an inflammatory pain rat model

Lee

Kim

et al. 2012

Mol Med Report

View full text Add to dashboard Cite

show abstract

“…RhoGDI␣ is phosphorylated by PAK1 at Ser101 and Ser174 and by PKA at Ser174 (26,27), and the phosphorylation events lead to dissociation and subsequent activation of Rac1 and RhoA. However, it is unclear how phosphorylation of RhoGDI␣ leads to the release of these GTPases.…”

Section: Discussionmentioning

confidence: 99%

“…RhoGDI␣-Ser174 has been shown to be phosphorylated by PAK1 and protein kinase A (PKA) (26,27), and this phosphorylation promotes its dissociation from either Rac1 or RhoA. Therefore, we speculated that 14-3-3 could associate with RhoGDI␣, and this binding led to the release of Rho GTPases from RhoGDI␣, promoting the activation of Rho GTPases upon ligand stimulation.…”

Section: -3-3 Promotes Cell Invasiveness and Reduces Adhesion Inmentioning

confidence: 99%

14-3-3τ Promotes Breast Cancer Invasion and Metastasis by Inhibiting RhoGDIα

Xiao

Lin

Shi

et al. 2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

c 14-3-3 is frequently overexpressed in breast cancer; however, whether it contributes to breast cancer progression remains undetermined. Here, we identify a critical role for 14-3-3 in promoting breast cancer metastasis, in part through binding to and inhibition of RhoGDI␣, a negative regulator of Rho GTPases and a metastasis suppressor. 14-3-3 binds Ser174-phosphorylated RhoGDI␣ and blocks its association with Rho GTPases, thereby promoting epidermal growth factor (EGF)-induced RhoA, Rac1, and Cdc42 activation. When 14-3-3 is overexpressed in MCF7 breast cancer cells that express 14-3-3 at low levels, it increases motility, reduces adhesion, and promotes metastasis in mammary fat pad xenografts. On the other hand, depletion of 14-3-3 in MCF7 cells and in an invasive cell line, MDA-MB231, inhibits Rho GTPase activation and blocks breast cancer migration and invasion. Moreover, 14-3-3 overexpression in human breast tumors is associated with the activation of ROCK (a Rho GTPase effector), high metastatic rate, and shorter survival, underscoring a clinically significant role for 14-3-3 in breast cancer progression. Our work indicates that 14-3-3 is a novel therapeutic target to prevent breast cancer metastasis.

show abstract

“…(32,33). Moreover, PKA activation in endothelial cells can result in inhibition of Rho kinase by direct phosphorylation of Rho GDPdissociation inhibitor (RhoGDI), thus preventing the release of the barrier-disruptive RhoA from the RhoA-RhoGDI complex (34). Besides, cAMP potentiates VE-cadherin-mediated cell-cell contacts, thus enhancing endothelial barrier function (32,33).…”

Section: Discussionmentioning

confidence: 99%

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

Lucas

Sridhar

Rick

et al. 2012

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

View full text Add to dashboard Cite

Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na + transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na + /K + -ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na + uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.pneumonia | cyclic AMP

show abstract

Phosphorylation of GTP dissociation inhibitor by PKA negatively regulates RhoA

Cited by 54 publications

References 43 publications

Phosphoproteomic analysis of electroacupuncture analgesia in an inflammatory pain rat model

Phosphoproteomic analysis of electroacupuncture analgesia in an inflammatory pain rat model

14-3-3τ Promotes Breast Cancer Invasion and Metastasis by Inhibiting RhoGDIα

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

Contact Info

Product

Resources

About