σ1B-adaptin sorts sortilin in adipose tissue regulating adipogenesis

Baltes, Jennifer; Larsen, Jakob Vejby; Radhakrishnan, Karthikeyan; Geumann, Constanze; Kratzke, Manuel; Petersen, Claus Munck; Schu, Peter

doi:10.1242/jcs.146886

Cited by 34 publications

(27 citation statements)

References 53 publications

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“…This observation may indirectly imply a possibility that cellular events that alter Sort1 trafficking process may be linked to Sort1 degradation. This is also supported by a recent study showing that altered AP-1-dependent Sort1 trafficking also affected cellular Sort1 protein degradation and Sort1 protein abundance without changes in Sort1 mRNA expression in adipocytes and in adipose tissue of mice (20). In addition, it is known that functional GSV formation depends on the key protein components to form a stable complex, and some experimental conditions that reduced GSV formation, such as by reducing Sort1 expression, also destabilized GLUT4 and caused GLUT4 degradation in adipocytes (16, 38).…”

Section: Resultssupporting

confidence: 79%

“…However, the in vivo role of Sort1 in adipose glucose metabolism seems to be more complex as mice lacking Sort1 globally showed reduced basal adipose glycolytic activity but normal insulin-stimulated adipose glucose uptake (19). Sort1 has also been shown to inhibit adipogenesis by regulating the intracellular trafficking of DLK1, a receptor that inhibits adipogenesis (20, 21), and increased adipose Sort1 expression decreases adipogenesis and adipose mass. This finding raises another question whether downregulation of adipose Sort1 in obesity helps promote adipose differentiation in response to higher dietary lipid uptake.…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking Sort1 maintained overall glucose homeostasis but showed reduced basal glycolytic activity in adipose tissue (19). More recently, it was reported that increased Sort1 expression repressed adipogenesis by regulating the trafficking and function of delta-like 1 homologue (DLK1), an inhibitor of adipocyte differentiation (20, 21). Whole body Sort1 knockout mice were not obese (19, 22).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes

Li¹,

Cheng²,

Li³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Sortilin 1(Sort1) is a vesicle trafficking receptor that mediates protein sorting in the endocytic and exocytic pathways. Sort1 is a component of the GLUT4 storage vesicles in adipocytes and is also involved in the regulation of adipogenesis. Sort1 protein is reduced in adipose of obese mice and humans, but the underlying cause is not fully understood. Here we report that insulin/PI3K/AKT signaling cascade critically regulates adipose Sort1 protein abundance. Administration of a PI3K inhibitor rapidly decreased Sort1 protein but not mRNA in adipose of chow-fed mice. In 3T3-L1 adipocytes, serum-starvation or inhibition of the PI3K/AKT signaling also decreased Sort1 protein without affecting Sort1 mRNA expression. Sort1 protein downregulation upon PI3K inhibition was blocked by pretreatment of MG132 but not Bafilomycin A1, suggesting that PI3K inhibition caused Sort1 degradation via the proteasome pathway. Using a phospho-specific Sort1 antibody, we showed that endogenous Sort1 was phosphorylated at S825 adjacent to the DXXLL sorting motif on the cytoplasmic tail. We demonstrated that mutagenesis that abolished Sort1 S825 phosphorylation decreased insulin-stimulated Sort1 localization on the plasma membrane and Sort1 protein stability in 3T3-L1 adipocytes. However, endogenous Sort1 phosphorylation at S825 was not affected by insulin stimulation or by inhibition of PI3K. In conclusion, this study revealed an important role of insulin signaling in regulating adipose Sort1 protein stability, and further suggests that impaired insulin signaling may underlie reduced adipose Sort1 in obesity. The cellular events downstream of insulin/PI3K/AKT signaling that mediates insulin regulation of Sort1 stability requires further investigation.

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Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes

Li¹,

Cheng²,

Li³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…A possible role for sortilin in body weight control is suggested by studies documenting protection from diet-induced obesity and from fatty liver disease (hepatic steatosis) in mice lacking this receptor 53 . Possible receptor functions implicated in these processes include the intracellular trafficking of acid sphingomyelinase, a modulator of insulin signaling in adipose tissue, or of delta-like 1 homologue, an inhibitor of adipogenesis 54 .…”

Section: Sortilin a Risk Factor For Hypercholesterolemia And Myocardmentioning

confidence: 99%

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

Schmidt

Willnow

2016

Atherosclerosis

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VPS10P domain receptors are a unique class of sorting receptors that direct intracellular transport of target proteins in neurons and that play central roles in neurodegenerative processes. Surprisingly, genome-wide association studies now implicate the very same receptors in cardiovascular and metabolic disturbances. In this review, we discuss current findings that uncovered some of the molecular mechanisms whereby sorting receptors, such as SORLA, sortilin, and SORCS1 control homeostasis in cardiovascular and metabolic tissues, and how they promote hypercholesterolemia, atherosclerosis, obesity, and diabetes, when being altered.3

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“…Two canonical sorting motifs in cytosolic tails of transmembrane proteins have been described for AP-1: the tyrosinebased motif YXXØ, which is bound by the 1A C-terminal domain, and the dileucine-based motifs (e.g. (D/E)XXXL(L/I), which are bound by 1A and/or 1B adaptins (25,26). L-selectin cytoplasmic tail does not contain either of these two sorting motifs.…”

Section: Discussionmentioning

confidence: 99%

The cytoplasmic tail of L-selectin interacts with the adaptor-protein complex AP-1 subunit μ1A via a novel basic binding motif

Dib

Tikhonova

Ivetic

et al. 2017

Journal of Biological Chemistry

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L-selectin regulates leukocyte adhesion and rolling along the endothelium. Proteins binding to the cytoplasmic tail of L-selectin regulate L-selectin functions. We used L-selectin cytoplasmic tail peptide pulldown assays combined with high sensitivity liquid chromatography/mass spectrometry to identify novel L-selectin tail-binding proteins. Incubation of the L-selectin tail with cell extracts from phorbol 12-myristate 13-acetate-stimulated Raw 264.7 macrophages resulted in the binding of μ1A of the clathrin-coated vesicle AP-1 complex. Furthermore, full-length GST-μ1A and the GST-μ1A C-terminal domain, but not the GST-μ1A N-terminal domain, bind to L-selectin tail peptide, and the intracellular pool of L-selectin colocalizes with AP-1 at the -Golgi network. We identified a novel basic protein motif consisting of a cluster of three dibasic residues (RR, KK, and KK) in the membrane-proximal domain of the L-selectin tail as well as a doublet of aspartic acid residues (DD) in the membrane-distal end of the L-selectin tail involved in μ1A binding. Stimulation of Raw 264.7 macrophages with PMA augmented the amount of μ1A associated with anti-L-selectin immunoprecipitates. However, full-length GST-μ1A did not bind to the phospho-L-selectin tail or phospho-mimetic S364D L-selectin tail. Accordingly, we propose that phosphorylation of μ1A is required for interaction with the L-selectin tail and that L-selectin tail phosphorylation may regulate this interaction Molecular docking of the L-selectin tail to μ1A was used to identify the μ1A surface domain binding the L-selectin tail and to explain how phosphorylation of the L-selectin tail abrogates μ1A interaction. Our findings indicate that L-selectin is transported constitutively by the AP-1 complex, leading to the formation of a-Golgi network reserve pool and that phosphorylation of the L-selectin tail blocks AP-1-dependent retrograde transport of L-selectin.

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σ1B-adaptin sorts sortilin in adipose tissue regulating adipogenesis

Cited by 34 publications

References 53 publications

Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes

Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3 T3-L1 adipocytes

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

The cytoplasmic tail of L-selectin interacts with the adaptor-protein complex AP-1 subunit μ1A via a novel basic binding motif

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