Limits...
"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.

Show MeSH
Shp-2 reduces endogenous ROS formation.                                        Endothelial cells were transfected with empty vector (EV), Shp-2 wt or                                        Shp-2(C459S) and endogenous ROS formation was measured using FACS analysis.                                        *p<0.05 versus Shp-2 wt. **p<0.05 versus EV. Data are means +/- SEM                                        (n=6).                                        The Western blot on the right demonstrates expression of Shp-2 wt and Shp-2(C459S), which were detected with anti-myc antibody.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2806037&req=5

Figure 1: Shp-2 reduces endogenous ROS formation. Endothelial cells were transfected with empty vector (EV), Shp-2 wt or Shp-2(C459S) and endogenous ROS formation was measured using FACS analysis. *p<0.05 versus Shp-2 wt. **p<0.05 versus EV. Data are means +/- SEM (n=6). The Western blot on the right demonstrates expression of Shp-2 wt and Shp-2(C459S), which were detected with anti-myc antibody.

Mentions: In 2002 Chughtai et al reported a nuclear localization of Shp-2 associated with the signal transducer and activator of transcription 5 (STAT5). The stimulation of mammary cells with prolactin induced the nuclear translocation of Shp-2 in a complex with STAT5. Formation of this complex and tyrosine phosphorylation of STAT5 in response to prolactin requires the SH2 domain closer to the C-terminus and the catalytic activity of Shp-2. The authors speculated that the nuclear Shp-2/STAT5 complex binds to DNA and regulates transcription of milk protein genes [2], demonstrating a transcriptional regulation by nuclear Shp-2. This provided for the first time evidence for a function of Shp-2 besides dephosphorylation. In contrast, it has been demonstrated that Shp-2 dephosphorylates STAT1 at tyrosine and serine residues in the nucleus and thereby inhibits its transcriptional activity [3]. One may speculate that depending on the mode of its action Shp-2 differently regulates specific STAT proteins. Just recently, we discovered that nuclear Shp-2 seems to be involved in aging processes. Previous findings from our group demonstrated that the enzyme Telomerase Reverse Transcriptase (TERT), which is important for maintaining telomere length and known to delay aging processes, when overexpressed, is tyrosine phosphorylated by Src kinases in the nucleus under conditions of oxidative stress in several cell types, including endothelial cells [4,5]. This tyrosine phosphorylation triggers nuclear export of TERT. Taking into account that cytosolic Shp-2 and the cytosolic Src kinase family can regulate and antagonize each other under certain conditions, we hypothesized that a nuclear Shp-2 also exists in endothelial cells and that this may counteract the Src kinase dependent nuclear export of TERT. Indeed, ablation of endogenous Shp-2 results in increased tyrosine phosphorylation of nuclear TERT and a reduction of telomerase activity in the nucleus. Moreover, overexpression of Shp-2 inhibited oxidative stress induced tyrosine phosphorylation and export of TERT from the nucleus. It has to be noted that this process requires the catalytic activity of Shp-2, since the catalytically inactive mutant Shp-2(C459S) can not pre- vent nuclear export of TERT. Interestingly, overexpression of Shp-2(C459S) reduced nuclear telomerase activity already under basal conditions. This effect was dependent on tyrosine 707 in TERT [6]. One possible explanation for the nuclear export of TERT induced by Shp-2(C459S) under basal conditions could be the significant increase in reactive oxygen species (ROS), which are known to activate the Src kinase family. Indeed, ROS formation is enhanced upon overexpression of Shp-2(C459S) in endothelial cells (Figure 1). These data point to a regulatory role of Shp-2 in the redox balance of cells.


"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 ROS formation.                                        Endothelial cells were transfected with empty vector (EV), Shp-2 wt or                                        Shp-2(C459S) and endogenous ROS formation was measured using FACS analysis.                                        *p<0.05 versus Shp-2 wt. **p<0.05 versus EV. Data are means +/- SEM                                        (n=6).                                        The Western blot on the right demonstrates expression of Shp-2 wt and Shp-2(C459S), which were detected with anti-myc antibody.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Shp-2 reduces endogenous ROS formation. Endothelial cells were transfected with empty vector (EV), Shp-2 wt or Shp-2(C459S) and endogenous ROS formation was measured using FACS analysis. *p<0.05 versus Shp-2 wt. **p<0.05 versus EV. Data are means +/- SEM (n=6). The Western blot on the right demonstrates expression of Shp-2 wt and Shp-2(C459S), which were detected with anti-myc antibody.
Mentions: In 2002 Chughtai et al reported a nuclear localization of Shp-2 associated with the signal transducer and activator of transcription 5 (STAT5). The stimulation of mammary cells with prolactin induced the nuclear translocation of Shp-2 in a complex with STAT5. Formation of this complex and tyrosine phosphorylation of STAT5 in response to prolactin requires the SH2 domain closer to the C-terminus and the catalytic activity of Shp-2. The authors speculated that the nuclear Shp-2/STAT5 complex binds to DNA and regulates transcription of milk protein genes [2], demonstrating a transcriptional regulation by nuclear Shp-2. This provided for the first time evidence for a function of Shp-2 besides dephosphorylation. In contrast, it has been demonstrated that Shp-2 dephosphorylates STAT1 at tyrosine and serine residues in the nucleus and thereby inhibits its transcriptional activity [3]. One may speculate that depending on the mode of its action Shp-2 differently regulates specific STAT proteins. Just recently, we discovered that nuclear Shp-2 seems to be involved in aging processes. Previous findings from our group demonstrated that the enzyme Telomerase Reverse Transcriptase (TERT), which is important for maintaining telomere length and known to delay aging processes, when overexpressed, is tyrosine phosphorylated by Src kinases in the nucleus under conditions of oxidative stress in several cell types, including endothelial cells [4,5]. This tyrosine phosphorylation triggers nuclear export of TERT. Taking into account that cytosolic Shp-2 and the cytosolic Src kinase family can regulate and antagonize each other under certain conditions, we hypothesized that a nuclear Shp-2 also exists in endothelial cells and that this may counteract the Src kinase dependent nuclear export of TERT. Indeed, ablation of endogenous Shp-2 results in increased tyrosine phosphorylation of nuclear TERT and a reduction of telomerase activity in the nucleus. Moreover, overexpression of Shp-2 inhibited oxidative stress induced tyrosine phosphorylation and export of TERT from the nucleus. It has to be noted that this process requires the catalytic activity of Shp-2, since the catalytically inactive mutant Shp-2(C459S) can not pre- vent nuclear export of TERT. Interestingly, overexpression of Shp-2(C459S) reduced nuclear telomerase activity already under basal conditions. This effect was dependent on tyrosine 707 in TERT [6]. One possible explanation for the nuclear export of TERT induced by Shp-2(C459S) under basal conditions could be the significant increase in reactive oxygen species (ROS), which are known to activate the Src kinase family. Indeed, ROS formation is enhanced upon overexpression of Shp-2(C459S) in endothelial cells (Figure 1). These data point to a regulatory role of Shp-2 in the redox balance of cells.

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