Internalization of CD40 regulates its signal transduction in vascular endothelial cells

Chen, Yali; Chen, Jianjun; Xiong, Yanbao; Da, Qi; Xu, Youli; Jiang, Xuejun; Tang, Hong

doi:10.1016/j.bbrc.2006.04.034

Cited by 65 publications

(47 citation statements)

References 47 publications

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“…Furthermore, trafficking of the receptor may also suggest thus far unknown spatial regulation of Fn14 signaling pathways. A signaling requirement for trafficking-induced compartmentalization has been described previously for other TNFRSF members, notably TNFR1 (59, 60) and CD40 (61,62).…”

Section: Discussionsupporting

confidence: 53%

Regulation of Fibroblast Growth Factor-inducible 14 (Fn14) Expression Levels via Ligand-independent Lysosomal Degradation

Winkles

Ghosh

et al. 2014

Journal of Biological Chemistry

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Background: Fn14 is a highly inducible TNF superfamily cytokine receptor. Results: Fn14 undergoes rapid, ligand-independent internalization and degradation mediated by the extracellular domain of the receptor. Conclusion: Fn14 expression is regulated through transcription as described previously and through a novel post-translational mechanism. Significance: Receptor trafficking may play an important role in regulating receptor availability, cytokine responses, and ligand-independent signaling.

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Section: Discussionsupporting

confidence: 53%

Regulation of Fibroblast Growth Factor-inducible 14 (Fn14) Expression Levels via Ligand-independent Lysosomal Degradation

Winkles

Ghosh

et al. 2014

Journal of Biological Chemistry

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“…Finally, TGZ induced Erk1/2 phosphorylation in LNCaP cells, which are deficient in PPARγ (Supplementary information, Fig-npg ure S1A). Taken together with the fact that the minimum concentration of TGZ required to elicit Erk1/2 phosphorylation (≥ 5 mM, data not shown) was much higher than its EC 50 for PPARγ-signaling activation [29], the aforementioned evidence strongly indicates that TGZ-activated Erk1/2 phosphorylation is independent of PPARγ in PAE-EGFR cells.…”

Section: Troglitazone Activated Egfr Signaling Independent Of Pparγmentioning

confidence: 85%

“…Total RNA extraction and real-time PCR conducted in an iCycler (BioRad) were performed using previously described methods [50]. Quantitative analysis was performed using the threshold procedure after normalizing to the expression of 18S RNA.…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor γ

Yang

et al. 2009

Cell Res

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Peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily of ligand-dependent transcription factors. Recent results have shown that agonists of PPARγ, such as troglitazone (TGZ), can inhibit cell proliferation and promote cell differentiation independent of PPARγ. In the present study, we provide evidence that TGZ may bind directly to EGFR and trigger its signaling and internalization independent of PPARγ. Detailed studies revealed that prolonged incubation with TGZ effectively attenuated EGFR signaling by targeting the receptor to the endo-lysosomal degradation machinery. Although the extracellular signal-regulated kinasesignaling pathway was transiently activated by TGZ in EGFR overexpressing cancer cells, inhibition of EGF-induced Akt phosphorylation most likely accounted for the growth arrest of tumor cells caused by TGZ at pharmacologically achievable concentrations. Therefore, we have provided a new line of evidence indicating that TGZ inhibits cell proliferation by promoting EGFR degradation and attenuating Akt phosphorylation.

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“…Fluorescence Microscopy-PAE cells in 35-mm plates were transfected with the plasmids indicated (1 g each) overnight and then seeded at 10 -20% confluence on 20-mm coverslips for an additional 24 h. Cells were then exposed or not to TGF-␤1 for 2 h and viewed directly with a fluorescence microscope (Nikon TE2000) for image analysis using a SlideBook 4.1 workstation (Intelligent Imaging Innovations, CO) as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

Pan

Qin

et al. 2010

Journal of Biological Chemistry

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Homeostasis of Smad phosphorylation at its C-terminal SXS motif is essential for transforming growth factor ␤ (TGF␤) signaling. Whereas it is known that TGF␤ signaling can be terminated by phosphatases, which dephosphorylate R-Smads in the nucleus, it is unclear whether there are any cytoplasmic phosphatase(s) that can attenuate R-Smad phosphorylation and nuclear translocation. Here we demonstrate that myotubularinrelated protein 4 (MTMR4), a FYVE domain-containing dualspecificity protein phosphatase (DSP), attenuates TGF␤ signaling by reducing the phosphorylation level of R-Smads in early endosomes. Co-immunoprecipitation experiments showed that endogenous MTMR4 interacts with phosphorylated R-Smads, and that this interaction is correlated with dephosphorylation of R-Smads. Further analysis showed that overexpression of MTMR4 resulted in the sequestration of activated Smad3 in the early endosomes, thus reducing its nuclear translocation. However, both point mutations at the conserved catalytic site of the phosphatase (MTMR4-C407S) and small interference RNA of endogenous Mtmr4 expression led to sustained Smad3 activation. This work therefore suggests that MTMR4 plays an important role in preventing the overactivation of TGF␤ signaling by dephosphorylating activated R-Smads that have been trafficked to early endosomes. The transforming growth factor ␤ (TGF␤)3 signaling pathway involves two transmembrane serine/threonine kinases, namely type II (T␤RII) and type I TGF␤ receptors (T␤RI) (1, 2). T␤RII, a constitutively active kinase, binds TGF␤ to initiate its heterodimerization with T␤RI. T␤RI then becomes phosphorylated and activates a signaling cascade through a family of intracellular signaling mediators known as Smads.In doing so, T␤RI recruits receptor-regulated Smads (RSmads, including BMP signaling transducers Smad1, -5, and -8 and TGF␤ signaling transducers Smad2, -3) and phosphorylates the two conserved C-terminal serines (SXS) of R-Smads. Activated R-Smads form a trimeric complex with a common mediator Smad (Co-Smad, Smad4), and these complexes translocate into the nucleus to regulate the transcription of an array of target genes (3-7). Recent studies have also indicated that Smad Anchor for Receptor Activation (SARA), an early endosomal protein containing a characteristic FYVE domain (Fab1p, YO1B, Vac1p, and EEA1), serves as an anchor protein by directly recruiting Smad2 to the early endosomes (8, 9) and presenting Smad2 to the internalized T␤RI/II complex (10, 11). Phosphorylated Smad2 then dissociates from SARA and leaves the early endosome. Subsequently, it forms a Smad2-Smad4 complex for nuclear translocation.Despite the fact that TGF␤ signaling activation is surprisingly simple, there are many layers of negative regulation that fine-tune or terminate the signal. The inhibitory Smads (I-Smads, including Smad6 and -7) competitively inhibit the interaction of R-Smads with Smad4 or receptors to provide a negative checkpoint for TGF␤-signaling activation (12). Ubiquitin-dependent degradation of activated...

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Internalization of CD40 regulates its signal transduction in vascular endothelial cells

Cited by 65 publications

References 47 publications

Regulation of Fibroblast Growth Factor-inducible 14 (Fn14) Expression Levels via Ligand-independent Lysosomal Degradation

Regulation of Fibroblast Growth Factor-inducible 14 (Fn14) Expression Levels via Ligand-independent Lysosomal Degradation

Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor γ

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

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