Induction of a Tumor-associated Activating Mutation in Protein Tyrosine Phosphatase Ptpn11 (Shp2) Enhances Mitochondrial Metabolism, Leading to Oxidative Stress and Senescence

Zheng, Hong; Li, Shanhu; Hsu, Peter L.; Qu, Cheng Kui

doi:10.1074/jbc.m113.462291

Cited by 38 publications

(31 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, we could determine that some markers of adipose tissue beiging were upregulated in adipose tissues from LS mice, notably in s.c. fat pads, suggesting that this adipose tissue has enhanced oxidative activity, which could contribute to enhanced energy expenditure. Interestingly, several studies have shown that SHP2 could regulate mitochondria activity, although the signaling pathways that link SHP2, and its LS-associated mutants, to the regulation of mitochondria function and energy homeostasis remain to be documented (37)(38)(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

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.

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 99%

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.

View full text Add to dashboard Cite

show abstract

“…It should be borne in mind that their activity is significantly affected by changes in the redox status of the environment, oxidation enhancing their activity, in sharp contrast with tyrosine phosphatases (PTPs), which are inhibited by oxidative stress (Giannoni and Chiarugi 2014). Thus, high levels of ROS lead to elevated tyrosine phosphorylation, with potentially dramatic changes in mitochondrial function (Zheng et al 2013). Interestingly, SFKs are also keys to reducing ROS levels by phosphorylating a component of complex II of the respiratory chain, i.e., flotillin-1 (Ogura et al 2014), which again emphasizes the importance of this class of enzymes as both regulators and effectors in mitochondrial physiology.…”

Section: Tyrosine Phosphorylation Ros Polyamines and Mitochondriamentioning

confidence: 98%

Pathophysiological implications of mitochondrial oxidative stress mediated by mitochondriotropic agents and polyamines: the role of tyrosine phosphorylation

et al. 2015

View full text Add to dashboard Cite

Mitochondria, once merely considered as the "powerhouse" of cells, as they generate more than 90 % of cellular ATP, are now known to play a central role in many metabolic processes, including oxidative stress and apoptosis. More than 40 known human diseases are the result of excessive production of reactive oxygen species (ROS), bioenergetic collapse and dysregulated apoptosis. Mitochondria are the main source of ROS in cells, due to the activity of the respiratory chain. In normal physiological conditions, ROS generation is limited by the anti-oxidant enzymatic systems in mitochondria. However, disregulation of the activity of these enzymes or interaction of respiratory complexes with mitochondriotropic agents may lead to a rise in ROS concentrations, resulting in oxidative stress, mitochondrial permeability transition (MPT) induction and triggering of the apoptotic pathway. ROS concentration is also increased by the activity of amine oxidases located inside and outside mitochondria, with oxidation of biogenic amines and polyamines. However, it should also be recalled that, depending on its concentration, the polyamine spermine can also protect against stress caused by ROS scavenging. In higher organisms, cell signaling pathways are the main regulators in energy production, since they act at the level of mitochondrial oxidative phosphorylation and participate in the induction of the MPT. Thus, respiratory complexes, ATP synthase and transition pore components are the targets of tyrosine kinases and phosphatases. Increased ROS may also regulate the tyrosine phosphorylation of target proteins by activating Src kinases or phosphatases, preventing or inducing a number of pathological states.

show abstract

“…It was demonstrated that low metastatic tumor cells have lower oxygen consumption than high metastatic tumors, including osteosarcoma. 30,31 Although many studies reported a shift from oxidative phosphorylation to glycolysis to provide energy for cellular activities in cancer cells, 32 cancer cells have also been reported to rely on oxidative phosphorylation and mitochondrial bioenergetics pathways for anabolism and energy production. 33 Our present finding indicates that PP2A Cα is involved in the regulation of mitochondrial respiratory capacity.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 2A Cα regulates proliferation, migration, and metastasis of osteosarcoma cells

Yang

Okamura

Morimoto

et al. 2016

Laboratory Investigation

View full text Add to dashboard Cite

Osteosarcoma is the most frequent primary bone tumor. Serine/threonine protein phosphatase 2A (PP2A) participates in regulating many important physiological processes, such as cell cycle, growth, apoptosis, and signal transduction. In this study, we examined the expression and function of PP2A Cα in osteosarcoma cells. PP2A Cα expression was expected to be higher in malignant osteosarcoma tissues. PP2A Cα expression level and PP2A activity was higher in malignant osteosarcoma LM8 cells compared with that in primary osteoblasts and in the osteoblast-like cell line MC3T3-E1. Okadaic acid, an inhibitor of PP2A, reduced cell viability and induced apoptosis in LM8 cells. PP2A Cα-knockdown LM8 cells (shPP2A) exhibited less striking filopodial and lamellipodial structures than that in original LM8 cells. Focal adhesion kinase phosphorylation and NF-κB activity decreased in shPP2A-treated cells. Sensitivity to serum deprivation-induced apoptosis increased in shPP2A-treated cells, accompanied by a lower expression level of anti-apoptotic BCL-2 in these cells. Reduction of PP2A Cα resulted in a decrease in the migration ability of LM8 cells in vitro. Reduction in PP2A Cα levels in vivo suppressed proliferation and metastasis in LM8 cells. PP2A Cα expression was also higher in human osteosarcoma MG63 and SaOS-2 cells than that in primary osteoblasts and MC3T3-E1 cells, and reduction in PP2A Cα levels suppressed the cell proliferation rate and migration ability of MG63 cells. These results indicate that PP2A Cα has a critical role in the proliferation and metastasis of osteosarcoma cells; therefore, its inhibition could potentially suppress the malignancy of osteosarcoma cells.

show abstract

Induction of a Tumor-associated Activating Mutation in Protein Tyrosine Phosphatase Ptpn11 (Shp2) Enhances Mitochondrial Metabolism, Leading to Oxidative Stress and Senescence

Cited by 38 publications

References 50 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

Pathophysiological implications of mitochondrial oxidative stress mediated by mitochondriotropic agents and polyamines: the role of tyrosine phosphorylation

Protein phosphatase 2A Cα regulates proliferation, migration, and metastasis of osteosarcoma cells

Contact Info

Product

Resources

About