Glial Cell Line–Derived Neurotrophic Factor and Its Receptor Ret Is a Novel Ligand-Receptor Complex Critical for Survival Response during Podocyte Injury

Tsui, Cynthia C.; Shankland, Stuart J.; Pierchala, Brian A.

doi:10.1681/asn.2005080835

Cited by 39 publications

(43 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We accomplished this by increasing or decreasing the amount of plasmid encoding GFP, depending on the number of molecules that were transfected in the various conditions. Immortalized mouse podocytes were maintained in vitro as described previously (Tsui et al, 2006). Flag-Cbl-3, Flag-Cbl-3 C351A, Flag-Cbl-3 G276E, and Flag-Cbl-3 TKB were kindly provided by Tadashi Yamamoto (University of Tokyo, Japan) (Kim et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

“…CD2AP and Cbl-3 expression was knocked down in sympathetic neurons using small interfering RNA (siRNA), similar to our previous study (Tsui et al, 2006). Control, CD2AP, and Cbl-3 siRNAs (Applied Biosystems/Ambion) were transfected into 4 DIV sympathetic neurons using the i-Fect reagent according to the manufacturer's instructions (Neuromics).…”

Section: Methodsmentioning

confidence: 99%

“…Glomeruli were purified from rodent kidneys, and the extent of Ret and CD2AP interaction was ascertained by coimmunoprecipitation studies. The majority of Ret expressed in podocytes, the only glomerular cell type that expresses Ret (Tsui et al, 2006), was associated with CD2AP ( Fig. 2 D, top).…”

Section: Cd2ap Associates With Inactive Ret and Dissociates From Actimentioning

confidence: 98%

“…Recent experiments indicate that Ret is highly expressed in podocytes, a cell type in the main filtering unit of the kidney known as the glomerulus (Tsui et al, 2006). Podocytes, which are also known as glomerular visceral epithelial cells, are critical in the formation and maintenance of the filtration barrier between blood and urine.…”

Section: Ret and Cd2ap Are Highly Colocalized In Podocytesmentioning

confidence: 99%

“…Part of the filtration barrier between blood and urine created by podocytes is composed of interdigitating foot processes that are linked together by a specialized structure called the slit diaphragm. In podocytes, the expression of Ret, as well as GDNF, is upregulated after their injury in vitro, as well as in animal models of glomerular diseases in vivo (Tsui et al, 2006). GDNF and Ret act as a protective response to podocyte injury, and they support the survival of podocytes in both injured and uninjured states (Tsui et al, 2006).…”

Section: Ret and Cd2ap Are Highly Colocalized In Podocytesmentioning

confidence: 99%

See 4 more Smart Citations

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

View full text Add to dashboard Cite

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are critical for nervous system development and maintenance. GFLs promote survival and growth via activation of the receptor tyrosine kinase (RTK) Ret. In sympathetic neurons, the duration of Ret signaling is governed by how rapidly Ret is degraded after its activation. In an effort to elucidate mechanisms that control the half-life of Ret, we have identified two novel Ret interactors, CD2-associated protein (CD2AP) and Cbl-3. CD2AP, an adaptor molecule involved in the internalization of ubiquitinated RTKs, is associated with Ret under basal, unstimulated conditions in neurons. After Ret activation by GDNF, CD2AP dissociates. Similarly, the E3-ligase Cbl-3 interacts with unphosphorylated Ret and dissociates from Ret after Ret activation. In contrast to their dissociation from autophosphorylated Ret, an interaction between CD2AP and Cbl-3 is induced by GDNF stimulation of sympathetic neurons, suggesting that CD2AP and Cbl-3 dissociate from Ret as a complex. In neurons, the overexpression of CD2AP enhances the degradation of Ret and inhibits GDNF-dependent survival, and gene silencing of CD2AP blocks Ret degradation and promotes GDNF-mediated survival. Surprisingly, Cbl-3 overexpression dramatically stabilizes activated Ret and enhances neuronal survival, even though Cbl-family E3 ligases normally function to trigger RTK downregulation. In combination with CD2AP, however, Cbl-3 promotes Ret degradation rapidly and almost completely blocks survival promotion by GDNF, suggesting that Cbl-3 acts as a switch that is triggered by CD2AP and oscillates between inhibition and promotion of Ret degradation. Consistent with the hypothesis, Cbl-3 silencing in neurons only inhibited Ret degradation and enhanced neuronal survival in combination with CD2AP silencing. CD2AP and Cbl-3, therefore, constitute a checkpoint that controls the extent of Ret downregulation and, thereby, the sensitivity of neurons to GFLs.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Cd2ap Associates With Inactive Ret and Dissociates From Actimentioning

confidence: 98%

Section: Ret and Cd2ap Are Highly Colocalized In Podocytesmentioning

confidence: 99%

Section: Ret and Cd2ap Are Highly Colocalized In Podocytesmentioning

confidence: 99%

See 3 more Smart Citations

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

View full text Add to dashboard Cite

show abstract

Bone marrow stromal cells protect oligodendrocytes from oxygen‐glucose deprivation injury

Zhang

Zheng

et al. 2008

J of Neuroscience Research

View full text Add to dashboard Cite

Oligodendrocyte (OLG) damage leads to demyelination, which is frequently observed in ischemic cerebrovascular diseases. In this study, we investigated the effect of bone marrow stromal cells (BMSCs) on OLGs subjected to oxygen-glucose deprivation (OGD). N20.1 cells (mouse OLG cell line) were transferred into an anaerobic chamber for 3 hr in glucose-free and serum-free medium. After OGD incubation, OLG cultures were divided into the following groups: 1) OGD alone, 2) OLG cocultured with BMSCs, 3) treatment with the phosphoinostide 3-kinase (PI3k) inhibitor LY294002, 4) LY294002-treated OLGs with BMSC cocultured, and 5) anti-p75 antibody-treated OLGs. After an additional 3 hr of reoxygenation incubation, OLG viability and apoptosis were measured. The mRNA expression in the BMSCs and OLGs was analyzed using quantitative real-time PCR (RT-PCR). Serine/threonine-specific protein kinase (Akt), phosphorylated Akt (p-Akt), p75, and caspase 3 protein expressions in OLGs were measured by Western blot. Our results suggest that BMSCs produce growth factors, activate the Akt pathway, and increase the survival of OLGs. BMSCs also reduce p75 and caspase 3 expressions in the OGD-OLGs, which leads to decreased OLG apoptosis. BMSCs participate in OLG protection that may occur with promoting growth factors/PI3K/Akt and inhibiting the p75/caspase pathways. Our study provides insight into white matter damage and the therapeutic benefits of BMSC-based remyelinating therapy after stroke and demyelinating diseases. Keywordsbone marrow stromal cells; oligodendrocytes; oxygen-glucose deprivation Oligodendrocytes (OLGs) generate the myelin sheaths that enwrap axons and thus play a pivotal role in the proper execution of neural function (Shibata et al., 2000). OLGs are very vulnerable to hypoxic and ischemic insults (Lyons and Kettenmann, 1998;Pantoni et al., 1996); damage to them leads to demyelination, which is frequently observed in ischemic cerebrovascular diseases and contributes to neurological functional impairment (Shibata et al., 2000;Li et al., 2005Li et al., , 2006Gresle et al., 2006). The precise mechanisms underlying the ischemia-induced death of OLGs are currently unknown (Shibata et al., 2000). Many factors determine the vulnerability of OLGs after ischemia (Dirnagl et al., 1999), such as caspases (Shibata et al., 2000), excitotoxicity (Matute et al., 2007), and oxidative stress (Imai et al., 2001). Therapeutic interventions are needed to protect OLGs as well as neurons and thereby to reduce neurological deficits after stroke. Our previous studies found that bone marrow Li et al., 2002;Zhang et al., 2004) and protected neural cells (i.e., neurons, astrocytes) from ischemic injury (Li et al., 2000Chopp and Li, 2002;Gao et al., 2005). However, the effect of BMSCs on ischemic OLGs has not been investigated.Growth factors bind to the tyrosine kinase receptors of neural cells, induce the production of phosphatidylinositol 3,4,5 [PtdIns(3,4,5)P3] by phosphoinostide 3-kinase (PI3K; Vlahos et al., 1994), activate the Akt ca...

show abstract

Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model

Jacobs

Leo

2013

J Neurooncol

View full text Add to dashboard Cite

Glioblastoma multiforme is one of the most common and aggressive primary brain tumors in adults. High glutamate levels are thought to contribute to glioma growth. While research has focused on understanding glutamate signaling in glioma cells, little is known about the role of glutamate between glioma and astrocyte interactions. To study the relationship between astrocytes and tumor cells, the CNS-1 rodent glioma cell line was used. We hypothesized increased glutamate uptake by astrocytes would negatively affect CNS-1 cell growth. Primary rodent astrocytes and CNS-1 cells were co-cultured for 7 days in a Boyden chamber in the presence of 5 mM glutamate. Cells were treated with propentofylline, an atypical synthetic methylxanthine known to increase glutamate transporter expression in astrocytes. Our results indicate astrocytes can increase glutamate uptake through the GLT-1 transporter, leading to less glutamate available for CNS-1 cells, ultimately resulting in increased CNS-1 cell apoptosis. These data suggest that astrocytes in the tumor microenvironment can be targeted by the drug, propentofylline.

show abstract

Glial Cell Line–Derived Neurotrophic Factor and Its Receptor Ret Is a Novel Ligand-Receptor Complex Critical for Survival Response during Podocyte Injury

Cited by 39 publications

References 28 publications

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Bone marrow stromal cells protect oligodendrocytes from oxygen‐glucose deprivation injury

Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model

Contact Info

Product

Resources

About