APPL Suppresses Androgen Receptor Transactivation via Potentiating Akt Activity

Yang, Lin; Lin, Hui Kuan; Altuwaijri, Saleh; Xie, Shusen; Wang, Liang; Chang, Chawnshang

doi:10.1074/jbc.m213163200

Cited by 56 publications

(58 citation statements)

References 36 publications

(45 reference statements)

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“…This protein contains multiple regulatory motifs that are involved in various signaling pathways. APPL1 is physically associated with several membrane receptors, such as follicle-stimulating hormone receptor (30) and androgen receptor (29), and the small GTPase Rab5 (38). In response to extracellular stimuli, such as epidermal growth factor and oxidative stress, APPL1 dissociates with Rab5 and translocates from membranes to the nucleus, where it interacts with nucleosome remodeling and histone deacetylase multiple protein complex NuRD/MeCP1, which in turn regulates chromatin structure and gene regulation (38).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have implicated the potential involvement of APPL1 in the regulation of phosphoinositide (PI) 3-kinase activity. APPL1 can directly interact with the regulatory subunit of PI 3-kinase (P85), and this interaction might be involved in androgen receptor-mediated activation of Akt (29). The selective PI 3-kinase inhibitors could abrogate adiponectin-evoked phosphorylation of AMPK at Thr 172 and of eNOS at Ser 1177 , and NO production in endothelial cells (12,15), suggesting that the activation of AMPK/eNOS by adiponectin is mediated by PI 3-kinase.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells

et al. 2007

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, and the complex formation between eNOS and heat shock protein 90, resulting in a marked reduction of NO production. Adenovirus-mediated overexpression of a constitutively active version of AMPK reversed these changes. In db/db diabetic mice, both APPL1 expression and adiponectin-induced vasodilation were significantly decreased compared with their lean littermates. Taken together, these results suggest that APPL1 acts as a common downstream effector of AdipoR1 and -R2, mediating adiponectin-evoked endothelial NO production and endothelium-dependent vasodilation. Diabetes 56: [1387][1388][1389][1390][1391][1392][1393][1394] 2007 E ndothelial dysfunction, characterized by decreased production and/or bioactivity of nitric oxide (NO) and impaired endothelium-dependent vasodilation, is a key mediator that links obesity, diabetes, and cardiovascular diseases (1). Dysfunction of the endothelium in conduit arteries is a well-established antecedent of hypertension and atherosclerosis, whereas dysfunction of peripheral vascular endothelium at the arteriolar and capillary level contributes to the pathogenesis of insulin resistance and the metabolic syndrome (2). On the other hand, insulin resistance aggravates endothelial dysfunction. Therapeutic interventions in animal models and humans have demonstrated that improving endothelial function ameliorates insulin resistance, while increasing insulin sensitivity alleviates endothelial dysfunction (3).Adiponectin, an insulin-sensitizing adipokine secreted predominantly from adipocytes, possesses potent protective effects against endothelial dysfunction (4). Unlike most adipokines, plasma levels of adiponectin are decreased in obese individuals and patients with insulin resistance, type 2 diabetes, and cardiovascular diseases. An independent association between serum levels of adiponectin and endothelium-dependent vasodilation has been repeatedly documented (5-7). Hypoadiponectinemia has been closely linked to impairment in endotheliumdependent vasodilation in both normal subjects and patients with hypertension and type 2 diabetes. Consistent with these clinical findings, adiponectin-deficient mice exhibit reduced endothelium-dependent vasodilation on an atherogenic diet (6), increased neointimal hyperplasia after acute vascular injury (8,9), and elevated blood pressure compared with their wild-type littermates (10). On the other hand, both adenovirus-mediated overexpression of full-length adiponectin and transgenic overexpression of globular adiponectin result in a marked alleviation of atherosclerotic lesion in apolipoprotein E-deficient mice (11) and also cause a significant amelioration of endothelial dysfunction and hypertension (10) in obese mice.The endothelium-protective functions of adiponectin are mediated, at least in part, by its ability to increase the production of NO, a vasodilator synthesized by endothelial NO synthase (eNOS) from the precursor L-arginine (4,7,12). NO protects the vascular system by enhancing vasodilation and inhibiting platelet aggregation,...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells

et al. 2007

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“…RACK1 has been previously shown to be a PKCanchoring protein that determines the localization of activated PKC␤II and has become widely perceived as a scaffolding protein coordinating the interaction of key signaling molecules (17). These findings combined with the fact that a number of scaffolding proteins including caveolin, filamin, and APPL are modulators of AR-mediated transactivation implicated a potential role for RACK1 in AR function (11,28,29). Our studies identify RACK1 as the first scaffolding protein required for ligand-independent AR nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

The Scaffolding Protein RACK1 Interacts with Androgen Receptor and Promotes Cross-talk through a Protein Kinase C Signaling Pathway

Rigas

Ozanne

Neal

et al. 2003

Journal of Biological Chemistry

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The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, functions as a ligand-dependent transcription factor that regulates genes involved in cell proliferation and differentiation. Using a C-terminal region of the human AR in a yeast two-hybrid screen, we have identified RACK1 (receptor for activated C kinase-1) as an AR-interacting protein. In this report we found that RACK1, which was previously shown to be a protein kinase C (PKC)-anchoring protein that determines the localization of activated PKC␤II isoform, facilitates ligand-independent AR nuclear translocation upon PKC activation by indolactam V. We also observed RACK1 to suppress ligand-dependent and -independent AR transactivation through PKC activation. In chromatin immunoprecipitation assays, we demonstrate a decrease in AR recruitment to the AR-responsive prostate-specific antigen (PSA) promoter following stimulation of PKC. Furthermore, prolonged exposure to indolactam V, a PKC activator, caused a reduction in PSA mRNA expression in prostate cancer LNCaP cells. Finally, we found PKC activation to have a repressive effect on AR and PSA protein expression in androgentreated LNCaP cells. Our data suggest that RACK1 may function as a scaffold for the association and modification of AR by PKC enabling translocation of AR to the nucleus but rendering AR unable to activate transcription of its target genes.

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“…The interaction between APPL1 and Akt is required for insulin-stimulated GLUT4 translocation (8) and for controlling Akt substrate selectivity (9). It has been shown that APPL1-potentiated Akt activity to suppress androgen receptor transactivation in prostate cancer cells (10). APPL1 has also been suggested to function as an adaptor protein in regulating follicle-stimulated hormone (FSH)-mediated PI 3-kinase/ Akt signaling pathway (11,12).…”

mentioning

confidence: 99%

Yin-Yang Regulation of Adiponectin Signaling by APPL Isoforms in Muscle Cells

Wang

Xin

Xiang

et al. 2009

Journal of Biological Chemistry

135

138

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APPL1 is a newly identified adiponectin receptor-binding protein that positively mediates adiponectin signaling in cells.Here we report that APPL2, an isoform of APPL1 that forms a dimer with APPL1, can interacts with both AdipoR1 and AdipoR2 and acts as a negative regulator of adiponectin signaling in muscle cells. Overexpression of APPL2 inhibits the interaction between APPL1 and AdipoR1, leading to down-regulation of adiponectin signaling in C2C12 myotubes. In contrast, suppressing APPL2 expression by RNAi significantly enhances adiponectin-stimulated glucose uptake and fatty acid oxidation. In addition to targeting directly to and competing with APPL1 in binding with the adiponectin receptors, APPL2 also suppresses adiponectin and insulin signaling by sequestrating APPL1 from these two pathways. In addition to adiponectin, metformin also induces APPL1-APPL2 dissociation. Taken together, our results reveal that APPL isoforms function as an integrated YinYang regulator of adiponectin signaling and mediate the crosstalk between adiponectin and insulin signaling pathways in muscle cells.Adiponectin, an adipocyte-secreted hormone that regulates energy homeostasis and insulin sensitivity, has been shown to be a promising therapeutic drug target for the treatment of type 2 diabetes (1-3). Adiponectin binds to its membrane receptors (AdipoR1 and AdipoR2) 3 and regulates lipid and glucose metabolism by activating downstream signaling molecules, such as AMP-activated protein kinase (AMPK), p38 MAP kinase (MAPK), and PPAR␣, in the muscle and liver (1, 4). Activation of AMPK by adiponectin reduces S6 kinase-mediated IRS-1 serine phosphorylation and increases IRS-1 tyrosine phosphorylation thus sensitizes insulin signaling in C2C12 myotubes (5), suggesting a direct cross-talk between the adiponectin and insulin signaling pathways.We have recently identified APPL1 (adaptor protein-containing PH domain, PTB domain, and leucine zipper motif) as a signaling protein immediately downstream of adiponectin receptors and positively mediates adiponectin signaling in muscle cells (6). This adaptor protein was previously shown to interact with the catalytic subunit of PI 3-kinase (p110) and Akt, which are two key kinases in the PI 3-kinase pathway downstream of the insulin receptor (7). The interaction between APPL1 and Akt is required for insulin-stimulated GLUT4 translocation (8) and for controlling Akt substrate selectivity (9). It has been shown that APPL1-potentiated Akt activity to suppress androgen receptor transactivation in prostate cancer cells (10). APPL1 has also been suggested to function as an adaptor protein in regulating follicle-stimulated hormone (FSH)-mediated PI 3-kinase/ Akt signaling pathway (11, 12). Our results showed that APPL1 binds directly to the intracellular part of the adiponectin receptors and positively mediates adiponectin signaling to the AMPK and p38 MAPK pathways, leading to increased glucose uptake and fatty acid oxidation in muscle cells (6). In addition, we found that APPL1 plays a critical ro...

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APPL Suppresses Androgen Receptor Transactivation via Potentiating Akt Activity

Cited by 56 publications

References 36 publications

Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells

Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells

The Scaffolding Protein RACK1 Interacts with Androgen Receptor and Promotes Cross-talk through a Protein Kinase C Signaling Pathway

Yin-Yang Regulation of Adiponectin Signaling by APPL Isoforms in Muscle Cells

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