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"Shping 2" different cellular localizations - a potential new player in aging processes.

Jakob S, Altschmied J, Haendeler J - Aging (Albany NY) (2009)

Bottom Line: For the recently found mitochondrial Shp-2 an involvement in the regulation of the cellular redox balance is discussed.Since a substantial fraction of TERT has been found in the mitochondria, it is hypothesized that mitochondrial Shp-2 acts as a positive regulator of TERT in the mitochondria, similar to its nuclear role.Taken together, Shp-2 seems to be a new player in aging processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell & Aging Research, IUF at the University of Duesseldorf gGmbH, 40225 Duesseldorf, Germany.

ABSTRACT
The functions of the ubiquitously expressed protein tyrosine phosphatase Shp-2 are dependent on its localization. Cytosolic Shp-2 is known to modulate different pathways involved in cell growth, cell development, tissue inflammation and cellular chemotaxis. But Shp-2 is also localized in the nucleus and the mitochondria. Nuclear Shp-2 forms a complex with the signal transducer and activator of transcription 5 (STAT5) which then binds to DNA and regulates transcription of milk genes. In contrast, nuclear Shp-2 dephosphorylates STAT1 and thereby inhibits gene transcription. In addition, it counteracts the oxidative stress dependent nuclear export of Telomerase Reverse Transcriptase (TERT) mediated by members of the Src kinase family, a process leading to replicative senescence. For the recently found mitochondrial Shp-2 an involvement in the regulation of the cellular redox balance is discussed. Shp-2 shows the ability to regulate reactive oxygen species formation in the mitochondria. There are hints that mitochondrial Shp-2 and Src are involved in the regulation of respiratory chain activity. Since a substantial fraction of TERT has been found in the mitochondria, it is hypothesized that mitochondrial Shp-2 acts as a positive regulator of TERT in the mitochondria, similar to its nuclear role. Taken together, Shp-2 seems to be a new player in aging processes.

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Shp-2 reduces endogenous mitochondrial ROS formation. Endothelial cells                                        were transfected with empty vector (EV) and Shp-2 wt. Mitochondrial ROS                                        formation was measured using mitosox and FACS analysis. *p<0.05 versus                                        EV. Data are means +/- SEM (n=3).
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Figure 2: Shp-2 reduces endogenous mitochondrial ROS formation. Endothelial cells were transfected with empty vector (EV) and Shp-2 wt. Mitochondrial ROS formation was measured using mitosox and FACS analysis. *p<0.05 versus EV. Data are means +/- SEM (n=3).

Mentions: Therefore, controlling ROS formation seems to be an interesting tool in delaying aging processes. It is tempting to speculate that nuclear Shp-2 plays an important role in nuclear based aging processes by reducing export of TERT from the nucleus and by reducing ROS formation (figure 1). However, we have also new hints, that Shp-2 may affect mitochondrial ROS production and thus, aging processes which depend on reduced mitochondrial function. New data from our laboratory demonstrate that overexpression of Shp-2 decreases not only ROS production in the cytosol (Figure 1) but also in the mitochondria (Figure 2). Moreover, preliminary results suggest that ablation of Shp-2 increases mitochondrial ROS levels. To specifically measure mitochondrial ROS levels, we used mitosox, a redox-sensitive dye, which first has to enter mitochondria before it can react with ROS. One can speculate, that the observed reduction of mitochondrially derived ROS is connected to a localization of Shp-2 in the mitochondria. Indeed, Salvi et al detected a tyrosine phosphatase activity in the mitochondria of rat brains and identified the responsible phosphatase as Shp-2 [8]. Recently, Arachiche et al showed also the mitochondrial localization of Shp-2 and of the tyrosine kinase Src, which is regulated by Shp-2 [9]. They demonstrated that the complexes of the respiratory chain are substrates of Src, which indicates that respiratory chain activity is partially dependent on tyrosine phosphorylation. Since Shp-2 is an important regulator of Src, Shp-2 is possibly involved in regulation of mitochondrial activity. In line with these findings, we recently demonstrated that TERT is localized in the mitochondria and importantly contributes to respiratory chain activity [10]. TERT deficient mice derived from heterozygous breeding pairs, which show no reduction in telomere length and thus no premature aging phenotype, demonstrated reduced respiratory chain activity in the heart, suggesting an important role for TERT in respiration in vivo [10]. Given the facts that Src kinase family members as well as Shp-2 show mitochondrial localization [9], it is tempting to speculate that similar to nuclear TERT also mitochondrial TERT is positively regulated by Shp-2 in these organelles. This could implicate that mitochondrial Shp-2 in concert with TERT accounts for an intact respiratory chain activity and for reduced mitochondrial ROS formation. Therefore, mitochondrial Shp-2 and TERT could break the above mentioned vicious cycle and thereby may delay aging processes, which depend on mitochondrial dysfunction.


"Shping 2" different cellular localizations - a potential new player in aging processes.

Jakob S, Altschmied J, Haendeler J - Aging (Albany NY) (2009)

Shp-2 reduces endogenous mitochondrial ROS formation. Endothelial cells                                        were transfected with empty vector (EV) and Shp-2 wt. Mitochondrial ROS                                        formation was measured using mitosox and FACS analysis. *p<0.05 versus                                        EV. Data are means +/- SEM (n=3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806037&req=5

Figure 2: Shp-2 reduces endogenous mitochondrial ROS formation. Endothelial cells were transfected with empty vector (EV) and Shp-2 wt. Mitochondrial ROS formation was measured using mitosox and FACS analysis. *p<0.05 versus EV. Data are means +/- SEM (n=3).
Mentions: Therefore, controlling ROS formation seems to be an interesting tool in delaying aging processes. It is tempting to speculate that nuclear Shp-2 plays an important role in nuclear based aging processes by reducing export of TERT from the nucleus and by reducing ROS formation (figure 1). However, we have also new hints, that Shp-2 may affect mitochondrial ROS production and thus, aging processes which depend on reduced mitochondrial function. New data from our laboratory demonstrate that overexpression of Shp-2 decreases not only ROS production in the cytosol (Figure 1) but also in the mitochondria (Figure 2). Moreover, preliminary results suggest that ablation of Shp-2 increases mitochondrial ROS levels. To specifically measure mitochondrial ROS levels, we used mitosox, a redox-sensitive dye, which first has to enter mitochondria before it can react with ROS. One can speculate, that the observed reduction of mitochondrially derived ROS is connected to a localization of Shp-2 in the mitochondria. Indeed, Salvi et al detected a tyrosine phosphatase activity in the mitochondria of rat brains and identified the responsible phosphatase as Shp-2 [8]. Recently, Arachiche et al showed also the mitochondrial localization of Shp-2 and of the tyrosine kinase Src, which is regulated by Shp-2 [9]. They demonstrated that the complexes of the respiratory chain are substrates of Src, which indicates that respiratory chain activity is partially dependent on tyrosine phosphorylation. Since Shp-2 is an important regulator of Src, Shp-2 is possibly involved in regulation of mitochondrial activity. In line with these findings, we recently demonstrated that TERT is localized in the mitochondria and importantly contributes to respiratory chain activity [10]. TERT deficient mice derived from heterozygous breeding pairs, which show no reduction in telomere length and thus no premature aging phenotype, demonstrated reduced respiratory chain activity in the heart, suggesting an important role for TERT in respiration in vivo [10]. Given the facts that Src kinase family members as well as Shp-2 show mitochondrial localization [9], it is tempting to speculate that similar to nuclear TERT also mitochondrial TERT is positively regulated by Shp-2 in these organelles. This could implicate that mitochondrial Shp-2 in concert with TERT accounts for an intact respiratory chain activity and for reduced mitochondrial ROS formation. Therefore, mitochondrial Shp-2 and TERT could break the above mentioned vicious cycle and thereby may delay aging processes, which depend on mitochondrial dysfunction.

Bottom Line: For the recently found mitochondrial Shp-2 an involvement in the regulation of the cellular redox balance is discussed.Since a substantial fraction of TERT has been found in the mitochondria, it is hypothesized that mitochondrial Shp-2 acts as a positive regulator of TERT in the mitochondria, similar to its nuclear role.Taken together, Shp-2 seems to be a new player in aging processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell & Aging Research, IUF at the University of Duesseldorf gGmbH, 40225 Duesseldorf, Germany.

ABSTRACT
The functions of the ubiquitously expressed protein tyrosine phosphatase Shp-2 are dependent on its localization. Cytosolic Shp-2 is known to modulate different pathways involved in cell growth, cell development, tissue inflammation and cellular chemotaxis. But Shp-2 is also localized in the nucleus and the mitochondria. Nuclear Shp-2 forms a complex with the signal transducer and activator of transcription 5 (STAT5) which then binds to DNA and regulates transcription of milk genes. In contrast, nuclear Shp-2 dephosphorylates STAT1 and thereby inhibits gene transcription. In addition, it counteracts the oxidative stress dependent nuclear export of Telomerase Reverse Transcriptase (TERT) mediated by members of the Src kinase family, a process leading to replicative senescence. For the recently found mitochondrial Shp-2 an involvement in the regulation of the cellular redox balance is discussed. Shp-2 shows the ability to regulate reactive oxygen species formation in the mitochondria. There are hints that mitochondrial Shp-2 and Src are involved in the regulation of respiratory chain activity. Since a substantial fraction of TERT has been found in the mitochondria, it is hypothesized that mitochondrial Shp-2 acts as a positive regulator of TERT in the mitochondria, similar to its nuclear role. Taken together, Shp-2 seems to be a new player in aging processes.

Show MeSH