The Adiponectin Receptors AdipoR1 and AdipoR2 Activate ERK1/2 through a Src/Ras-Dependent Pathway and Stimulate Cell Growth

Lee, Mi-Hye; Klein, Richard L.; El‐Shewy, Hesham M.; Luttrell, Deirdre K.; Luttrell, Louis M.

doi:10.1021/bi801451f

Cited by 113 publications

(96 citation statements)

References 42 publications

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“…Furthermore, these investigators showed a similar response occurred in endothelial and HEK293 cells and that adiponectin stimulated the proliferation of HEK293 cells (Lee et al 2008).…”

Section: Discussionmentioning

confidence: 74%

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Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Fuerst¹,

Taylor²,

Wright³

et al. 2012

Journal of Endocrinology

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Accelerated atherosclerosis is the primary cardiovascular manifestation of diabetes and correlates inversely with levels of circulating adiponectin, an anti-atherosclerotic adipokine that declines in diabetes. We therefore initiated a study to examine the mechanisms by which adiponectin, a hormone released from adipose tissue, influences the proliferation of vascular smooth muscle cells (SMCs). Addition of adiponectin to quiescent porcine coronary artery SMCs increased both protein and DNA synthesis and concurrently activated ERK1/2 and Akt. By contrast, globular adiponectin, a truncated form of this protein, exhibited anti-mitogenic properties as indicated by the inhibition of protein and DNA synthesis in SMCs stimulated with platelet-derived growth factor (PDGF). Whereas globular adiponectin did not stimulate growth-related signal transduction pathways, it was able to block the PDGF-dependent phosphorylation of eukaryotic elongation factor 2 kinase, a regulator of protein synthesis. Proteolysis of adiponectin with trypsin, which produces globular adiponectin, reversed the growth-stimulating actions of the undigested protein. As the existence of globular adiponectin remains controversial, western blotting was used to establish its presence in rat serum. We found that globular adiponectin was detectable in rat serum, but this result was not obtained with all antibodies. The contrasting properties of adiponectin and its globular form with respect to SMC proliferation suggest that protection against atherosclerosis may therefore be mediated, in part, by the level of globular adiponectin.

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“…Furthermore, these investigators showed a similar response occurred in endothelial and HEK293 cells and that adiponectin stimulated the proliferation of HEK293 cells (Lee et al 2008).…”

Section: Discussionmentioning

confidence: 74%

“…In contrast to these observations, however, Lee et al (2008) reported that treatment of SMCs with adiponectin resulted in ERK1/2 activation. Furthermore, these investigators showed a similar response occurred in endothelial and HEK293 cells and that adiponectin stimulated the proliferation of HEK293 cells (Lee et al 2008).…”

Section: Discussionmentioning

confidence: 79%

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Fuerst¹,

Taylor²,

Wright³

et al. 2012

Journal of Endocrinology

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“…45 Both contain seven transmembrane domains but are structurally and functionally distinct from G-protein-coupled receptors. Unlike G-proteincoupled receptors, the amino (N)-termini of both receptors are intracellular and the C-terminal end is extracellular and binds adiponectin.…”

Section: Adiponectin Mediates Crosstalk Between Adipose Kidney and mentioning

confidence: 99%

Mechanisms Linking Obesity, Chronic Kidney Disease, and Fatty Liver Disease

Sharma

2010

Journal of the American Society of Nephrology

314

213

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“…In endothelial cells, adiponectin can activate AMPactivated protein kinase through APPL1 to provide a survival signal (15). Alternatively, adiponectin activates the ERK pathway through APPL-dependant Ras activation (16). Nevertheless, APPL mediates the adiponectin-induced phosphorylation of endothelial nitric-oxide synthase, and the subsequent production of nitric oxide that triggers endothelium-dependent vasodilation (17).…”

mentioning

confidence: 99%

Appl1 Is Dispensable for Mouse Development, and Loss of Appl1 Has Growth Factor-selective Effects on Akt Signaling in Murine Embryonic Fibroblasts

Tan

You

et al. 2010

Journal of Biological Chemistry

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The adaptor protein APPL1 (adaptor protein containing pleckstrin homology (PH), phosphotyrosine binding (PTB), and leucine zipper motifs) was first identified as a binding protein of AKT2 by yeast two-hybrid screening. APPL1 was subsequently found to bind to several membrane-bound receptors and was implicated in their signal transduction through AKT and/or MAPK pathways. To determine the unambiguous role of Appl1 in vivo, we generated Appl1 knock-out mice. Here we report that Appl1 knock-out mice are viable and fertile. The adaptor protein containing pleckstrin homology (PH), phosphotyrosine binding (PTB), and leucine zipper motifs (APPL) 5 was first identified as an AKT2-interacting protein by yeast two-hybrid screening (1). APPL1, also dubbed DIP13␣ (DCC-interacting protein 13␣) (2), comprises three domains, i.e. Bar, PH, and PTB motifs. Whereas all of these domains can bind to lipids, each has unique binding preferences, which theoretically enables APPL to bind to various signaling proteins. The membrane binding-bending feature of the APPL protein permits it to be trafficked among many subcellular compartments (3). Moreover, the APPL Bar domain interacts with its own PH domain to form a unique Bar-PH structure that distinguishes APPL from other Bar domain-containing molecules (4). We previously showed that APPL1 can bind to AKT2 through its PTB domain (1), and subsequent co-immunoprecipitation studies showed that APPL1 also binds to AKT1, AKT3, and the p110 catalytic subunit of phosphatidylinositol 3-kinase. APPL1 does not bind to phosphorylated (active) AKT, and our initial report did not ascertain whether binding to APPL1 affects AKT activity (1). Subsequent work identified a second APPL protein, APPL2, which shares a high homology with APPL1 as well as some of the same binding partners (5).The function of APPL proteins was first demonstrated in HeLa cells, where APPL1 and APPL2 were found to represent key signaling links from the endosome to the nucleus by switching and activating binding partners from the small GTPase Rab5 on endosomes to the nucleosome remodeling and histone deacetylase multiprotein complex NuRD-MeCP1. Furthermore, knock down of APPL protein inhibited DNA synthesis and resulted in cell cycle arrest (6). Structural analysis revealed that APPL binds to Rab5 mainly through its PH domain, but the Bar domain at the other side of the dimer also binds to Rab5 (7). A broader role for APPL in signal transduction was soon discovered when various groups found that APPL proteins are implicated in nerve growth factor and follicle stimulating hormone signaling, as well as in lipid and glucose metabolism. Two groups independently reported that APPL1 tethers GIPC1 to * This work was supported, in whole or in part, by National Institutes of Health Grants CA77429 (to J. R. T.) and CA06927 (to Fox Chase Cancer Center) from the NCI and an appropriation from the Commonwealth of Pennsylvania. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedur...

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The Adiponectin Receptors AdipoR1 and AdipoR2 Activate ERK1/2 through a Src/Ras-Dependent Pathway and Stimulate Cell Growth

Cited by 113 publications

References 42 publications

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Mechanisms Linking Obesity, Chronic Kidney Disease, and Fatty Liver Disease

Appl1 Is Dispensable for Mouse Development, and Loss of Appl1 Has Growth Factor-selective Effects on Akt Signaling in Murine Embryonic Fibroblasts

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