Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase

He, Zhao; Zhu, Helen He; Bauler, Timothy J.; Wang, Jing; Ciaraldi, Theodore P.; Alderson, Nazilla; Li, Shuangwei; Raquil, Marie Astrid; Ji, Kaihong; Wang, Shufen; Shao, Jianhua; Henry, Robert R.; King, Philip D.; Feng, Gen Sheng

doi:10.1073/pnas.1213000110

Cited by 48 publications

(55 citation statements)

References 66 publications

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“…First, we have shown that LS-causing mutation reduces the differentiation of SVF-derived cells into adipocytes, suggesting a defect in adipogenesis. Supporting this view, aP2-Cre-mediated Ptpn11 invalidation in adipose tissue strongly impairs adipose tissue development, and SHP2 knockdown in a preadipocyte cell line or in pluripotent embryonic stem cells strongly inhibited adipocyte differentiation (29,30). Defective adipogenesis could result from dysregulation of specific signaling pathways in adipocyte precursors, notably p38, as proposed by He et al (30) or MAPK ERK1/2 (32), but also from inappropriate production of adipogenesis-regulating factors.…”

Section: Discussionmentioning

confidence: 69%

“…Supporting this view, aP2-Cre-mediated Ptpn11 invalidation in adipose tissue strongly impairs adipose tissue development, and SHP2 knockdown in a preadipocyte cell line or in pluripotent embryonic stem cells strongly inhibited adipocyte differentiation (29,30). Defective adipogenesis could result from dysregulation of specific signaling pathways in adipocyte precursors, notably p38, as proposed by He et al (30) or MAPK ERK1/2 (32), but also from inappropriate production of adipogenesis-regulating factors. Of note, more general determination processes might be impaired in LS mice, because SHP2 has been shown to control stem cell development (33,34).…”

Section: Discussionmentioning

confidence: 69%

“…Indeed, a positive role for SHP2 in adipogenesis has already been identified in vitro and in vivo (29,30). We isolated the stroma vascular fraction (SVF) from epididymal and s.c. adipose tissues of WT and LS mice and challenged the ability of SVF-derived preadipocytes to differentiate into adipocytes in vitro.…”

Section: Ptpn11mentioning

confidence: 99%

“…Moreover, in muscle and in liver, SHP2 appears to differently modulate insulin sensitivity, although it also promotes insulin biosynthesis in the pancreas, uncovering a complex role of SHP2 in tuning glucose homeostasis (25)(26)(27)(28). Finally, recent studies have revealed a potential, albeit controversial, role for SHP2 in regulating adipogenesis in vitro and in vivo (29)(30)(31).…”

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confidence: 99%

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LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

Tajan

Batut

Cadoudal

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.rasopathies | ras/MAPK | energy metabolism | adipose tissue

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 69%

Section: Ptpn11mentioning

confidence: 99%

mentioning

confidence: 99%

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LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

Tajan

Batut

Cadoudal

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Spry2 constructs were previously described (3). FLAG-tagged Shp2 constructs (the wild type [WT], a D61A constitutively active mutant, and a C463S substrate trapping, dominant negative mutant) were kindly provided by G.-S. Feng (University of California at San Diego) (16). VN-Shp2 truncation mutants were kindly provided by Graeme Carnegie and consist of the following amino acids of Shp2: N-SH2, 1 to 103; C-SH2, 111 to 218; NϩC-SH2, 1 to 218; C-term, 219 to 597.…”

Section: Methodsmentioning

confidence: 99%

Receptor Tyrosine Kinase Ubiquitylation Involves the Dynamic Regulation of Cbl-Spry2 by Intersectin 1 and the Shp2 Tyrosine Phosphatase

Okur

Russo

O’Bryan

2014

Molecular and Cellular Biology

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Ubiquitylation of receptor tyrosine kinases (RTKs) regulates their trafficking and lysosomal degradation. The multidomain scaffolding protein intersectin 1 (ITSN1) is an important regulator of this process. ITSN1 stimulates ubiquitylation of the epidermal growth factor receptor (EGFR) through enhancing the activity of the Cbl E3 ubiquitin ligase. However, the precise mechanism through which ITSN1 enhances Cbl activity is unclear. Here, we demonstrate that ITSN1 interacts with and recruits the Shp2 tyrosine phosphatase to Spry2 to enhance its dephosphorylation, thereby disrupting the inhibitory effect of Spry2 on Cbl and enhancing EGFR ubiquitylation. In contrast, expression of a catalytically inactive Shp2 mutant reversed the effect of ITSN1 on Spry2 dephosphorylation and decreased Cbl-mediated EGFR ubiquitylation. In addition, disruption of ITSN1 binding to Spry2 through point mutation of the Pro-rich ITSN1 binding site in Spry2 resulted in decreased Shp2-Spry2 interaction and enhanced Spry2 tyrosine phosphorylation. This study demonstrates that ITSN1 enhances Cbl activity, in part, by modulating the interaction of Cbl with Spry2 through recruitment of Shp2 phosphatase to the Cbl-Spry2 complex. These findings reveal a new level of complexity in the regulation of RTKs by Cbl through ITSN1 binding with Shp2 and Spry2.

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Noonan syndrome patients beyond the obvious phenotype: A potential unfavorable metabolic profile

Noronha

Villares

Torres

et al. 2020

American J of Med Genetics Pt A

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Noonan syndrome (NS) and NS related disorders (NRD) are frequent monogenic diseases. Pathogenic variants in PTPN11 are observed in approximately 50% of these NS patients. Several pleiotropic phenotypes have previously been described in this condition. This study aimed at characterizing glucose and lipid profiles in patients with NS/NRD. We assessed fasting blood glucose, insulin, cholesterol (total and fractions), and triglyceride (TG) levels in 112 prepubertal children and 73 adults. Additionally, an oral glucose tolerance test (OGTT) was performed in 40 children and 54 adults. Data were analyzed between age groups according to the presence (+) or absence (−) of PTPN11 mutation. Prepubertal patients with NS/NRD were also compared with a control group. Despite the lean phenotype of children with NS/NRD, they presented an increased frequency of low HDL‐cholesterol (63% in PTPN11+, 59% in PTPN11‐ and 16% in control, p < .001) and high TG levels (29% in PTPN11+, 18% in PTPN11‐ and 2.3% in control). PTPN11+ patients had a higher median HOMA‐IR (1.0, ranged from 0.3 to 3.2) in comparison with PTPN11‐ (0.6; 0.2 to 4.4) and controls (0.6; 0.4 to 1.4, p = .027). Impaired glucose tolerance was observed in 19% (10:54) of lean adults with NS/NRD assessed by OGTT. Moreover, women with PTPN11 mutations had lower HDL‐cholesterol levels than those without. Our results suggest that children and young adult patients with NS/NRD have an unfavorable metabolic profile characterized by low HDL, a tendency of elevated TGs, and glucose metabolism impairment despite a lean phenotype.

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Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase

Cited by 48 publications

References 66 publications

LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

Receptor Tyrosine Kinase Ubiquitylation Involves the Dynamic Regulation of Cbl-Spry2 by Intersectin 1 and the Shp2 Tyrosine Phosphatase

Noonan syndrome patients beyond the obvious phenotype: A potential unfavorable metabolic profile

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