Development of Diabesity in Mice with Neuronal Deletion of Shp2 Tyrosine Phosphatase

Krajewska, Maryla; Banares, Steven; Zhang, Eric Erquan; Huang, Xianshu; Scadeng, Miriam; Jhala, Ulupi S.; Feng, Gen‐Sheng; Krajewski, Stan

doi:10.2353/ajpath.2008.070594

Cited by 59 publications

(57 citation statements)

References 39 publications

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“…9E). A number of studies have shown that mice lacking expression of SHP-2 either peripherally or centrally exhibit a variety of metabolic defects (64)(65)(66)(67). Altered mTORC1 signaling in these scenarios could contribute to these metabolic defects, given the important role of mTORC1/S6K1 in metabolism (1).…”

Section: Discussionmentioning

confidence: 99%

Novel Role for SHP-2 in Nutrient-Responsive Control of S6 Kinase 1 Signaling

Mercan

Lee

Kolli

et al. 2013

Molecular and Cellular Biology

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Amino acids are required for the activation of the mammalian target of rapamycin complex 1 (mTORC1), which plays a critical role in cell growth, proliferation, and metabolism. The branched-chain amino acid leucine is an essential nutrient that stimulates mTORC1 to promote protein synthesis by activating p70 S6 kinase 1 (S6K1). Here we show that the protein tyrosine phosphatase SHP-2 is required for leucine-induced activation of S6K1 in skeletal myoblasts. In response to leucine, S6K1 activation is inhibited in myoblasts either lacking SHP-2 expression or overexpressing a catalytically inactive mutant of SHP-2. Activation of S6K1 by leucine requires the mobilization of intracellular calcium (Ca 2؉ ), which we show is mediated by SHP-2 in an inositol-1,4,5-trisphosphate-dependent manner. Ectopic Ca 2؉ mobilization rescued the S6K1 activation defect in SHP-2-deficient myoblasts. SHP-2 was identified to act upstream of phospholipase C ␤4, linking it to the generation of nutrient-induced Ca 2؉ release and S6K1 phosphorylation. Consistent with these results, SHP-2-deficient myoblasts exhibited impaired leucine sensing, leading to defective autophagy and reduced myoblast size. These data define a new role for SHP-2 as a nutrient-sensing regulator in skeletal myoblasts that is required for the activation of S6K1.

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Section: Discussionmentioning

confidence: 99%

Novel Role for SHP-2 in Nutrient-Responsive Control of S6 Kinase 1 Signaling

Mercan

Lee

Kolli

et al. 2013

Molecular and Cellular Biology

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“…With regard to the mammalian enzyme, stimulatory mutations of the human gene have been found responsible for several abnormalities, such as the pathological activity of Helicobacter pylori ( 54 ), Noonan syndrome ( 33 ), leukemogenesis ( 55 ), and human breast cancer ( 56,57 ). Although the relationship between SHP2 and hormonal imbalance has been analyzed, particularly in diabetes (58)(59)(60), the role of SHP2 in these disorders is not yet fully described or understood. Here we report a new physiological role of SHP2 in hormone action, particularly in the hormonal activation of steroidogenesis.…”

Section: Role Of Acsl4 In Shp2-mediated Effect On Camp-stimulated Stementioning

confidence: 99%

Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4

Cooke¹,

Orlando²,

Maloberti

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org substrate preferences, enzyme kinetics, cellular and organelle locations, and regulation. ACSL4 has a marked preference for 20:4 (arachidonic acid, AA) and 20:5 (eicosapentaenoic acid). The high affi nity of ACSL4 for these fatty acids and the low affi nity for palmitic acid suggest that the enzyme plays a key role in the metabolism of AA. A second interesting feature of ACSL4 is its tissue distribution. In rats, its mRNA is expressed in various tissues, including the adrenal gland, epididymis, brain, lung, ovary, placenta, liver, and testis ( 6, 7 ). The striking feature of ACSL4 is its abundance in steroidogenic tissues, especially in zona fasciculata and reticularis of the rat adrenal gland, Leydig cells of the testis, and luteinized cells of the ovary ( 7 ). It is interesting that although relatively low or null expression levels of ACSL4 have been reported in other adult tissues ( 6, 7 ), this isoform is overexpressed in breast, prostate, colon, and liver cancer specimens ( 8-10 ).Regarding its function , ACSL4 is related to the acute regulation of steroid production in steroidogenic tissues. ACSL4 is a key protein ( 11 ) that works in concert with a mitochondrial acyl-CoA thioesterase, ACOT2 ( 12, 13 ). These two fatty acid-metabolizing enzymes constitute an AA generation/export system, which releases AA in the mitochondrion after the action of the steroidogenic hormones adrenocorticotropin hormone (ACTH) and luteinizing hormone (LH)/ chorionic gonadotropin (CG) ( 14 ). AA is then metabolized to lipoxygenated or epoxygenated products to induce the expression of the steroidogenesis acute regulatory (StAR) gene. StAR is a mitochondrial protein that, together with other proteins, participates in cholesterol transport to the inner mitochondrial membrane, which constitutes the rate-limiting Abstract Acyl-CoA synthetase 4 (ACSL4) is implicated in fatty acid metabolism with marked preference for arachidonic acid (AA). ACSL4 plays crucial roles in physiological functions such as steroid synthesis and in pathological processes such as tumorigenesis. However, factors regulating ACSL4 mRNA and/or protein levels are not fully described. Because ACSL4 protein expression requires tyrosine phosphatase activity, in this study we aimed to identify the tyrosine phosphatase involved in ACSL4 expression. NSC87877, a specifi c inhibitor of the tyrosine phosphatase SHP2, reduced ACSL4 protein levels in ACSL4-rich breast cancer cells and steroidogenic cells. Indeed, overexpression of an active form of SHP2 increased ACSL4 protein levels in MA-10 Leydig steroidogenic cells. SHP2 has to be activated through a cAMP-dependent pathway to exert its effect on ACSL4. The effects could be specifi cally attributed to SHP2 because knockdown of the phosphatase reduced ACSL4 mRNA and protein levels. Through the action on ACSL4 protein levels, SHP2 affected AA-CoA production and metabolism and, fi nally, the steroidogenic capacity of MA-10 cells: overexpression (or knockdown) of SHP2 led ...

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“…Potential causes include infectious agents, exposure to other environmental and dietary factors, hormonal and metabolic derangements, or a combination thereof. Animal models have provided a great deal of information about an association between metabolic diseases and LUT alterations (Azadzoi et al 1999, Kozlowski et al 2001, Krajewska et al 2008. Our laboratory has developed, over the last few years, an animal model of metabolic syndrome-associated hypogonadotropic hypogonadism by feeding adult male rabbits a high fat diet (HFD) for 12 weeks (Filippi et al 2009, Vignozzi et al 2011.…”

Section: Introductionmentioning

confidence: 99%

Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells

Vignozzi

Cellai²,

Santi³

et al. 2012

Journal of Endocrinology

126

107

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Progression of benign prostatic hyperplasia (BPH) involves chronic inflammation and immune dysregulation. Preclinical studies have demonstrated that prostate inflammation and tissue remodeling are exacerbated by hypogonadism and prevented by testosterone supplementation. We now investigated whether, in humans, hypogonadism was associated with more severe BPH inflammation and the in vitro effect of the selective androgen receptor agonist dihydrotestosterone (DHT) on cultures of stromal cells derived from BPH patients (hBPH). Histological analysis of inflammatory infiltrates in prostatectomy specimens from a cohort of BPH patients and correlation with serum testosterone level was performed. Even after adjusting for confounding factors, hypogonadism was associated with a fivefold increased risk of intraprostatic inflammation, which was also more severe than that observed in eugonadal BPH patients. Triggering hBPH cells by inflammatory stimuli (tumor necrosis factor a, lipopolysaccharide, or CD4 C T cells) induced abundant secretion of inflammatory/growth factors (interleukin 6 (IL6), IL8, and basic fibroblast growth factor (bFGF)). Co-culture of CD4 C T cells with hBPH cells induced secretion of Th1 inducer (IL12), Th1-recruiting chemokine (interferon g inducible protein 10, IP10), and Th2 (IL9)-and Th17 (IL17)-specific cytokines. Pretreatment with DHT inhibited NF-kB activation and suppressed secretion of several inflammatory/growth factors, with the most pronounced effects on IL8, IL6, and bFGF. Reduced inflammatory cytokine production by testosterone cells, an increase in IL10, and a significant reduction of testosterone cells proliferation suggested that DHT exerted a broad antiinflammatory effect on testosterone cells. In conclusion, our data demonstrate that DHT exerts an immune regulatory role on human prostatic stromal cells, inhibiting their potential to actively induce and/or sustain autoimmune and inflammatory responses.

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Development of Diabesity in Mice with Neuronal Deletion of Shp2 Tyrosine Phosphatase

Cited by 59 publications

References 39 publications

Novel Role for SHP-2 in Nutrient-Responsive Control of S6 Kinase 1 Signaling

Novel Role for SHP-2 in Nutrient-Responsive Control of S6 Kinase 1 Signaling

Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4

Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells

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