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PMID:18385140

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Citation

Rardin, MJ, Wiley, SE, Murphy, AN, Pagliarini, DJ and Dixon, JE (2008) Dual specificity phosphatases 18 and 21 target to opposing sides of the mitochondrial inner membrane. J. Biol. Chem. 283:15440-50

Abstract

Although large-scale approaches have identified numerous mitochondrial phosphoproteins, little is known about the mitochondrial kinases and phosphatases that regulate these phosphoproteins. Here, we identify two members of the atypical dual specificity phosphatases (DSP), DSP18 and DSP21, that are localized in mitochondria. Although DSP18 is widely expressed in several mammalian tissues, DSP21 is selectively expressed in the testes. We demonstrate that DSP18 and DSP21 are targeted to mitochondria by cryptic internal localization signals. Subfractionation of mitochondria demonstrated that DSP18 is located in the intermembrane space as a peripheral membrane protein of the inner membrane. In contrast, subfractionation of rat testis mitochondria revealed DSP21 is localized to the matrix as a peripheral membrane protein of the inner membrane. Moreover, we demonstrate that a previously reported substrate for DSP18, the stress-activated protein kinase, does not localize to mitochondria in several different tissues, making it an unlikely substrate for DSP18. Finally, we show that induction of apoptosis by treatment with staurosporine causes translocation of DSP18 from the intermembrane space into the cytosol similar to other apoptogenic factors such as cytochrome c. This work rigorously demonstrates the unique location of two highly similar DSPs on opposing sides of the mitochondrial inner membrane.

Links

PubMed PMC2397459 Online version:10.1074/jbc.M709547200

Keywords

Animals; Apoptosis/drug effects; Apoptosis/physiology; COS Cells; Cercopithecus aethiops; Cytochromes c/metabolism; Cytosol/enzymology; Cytosol/ultrastructure; Dual-Specificity Phosphatases/metabolism; Enzyme Inhibitors/pharmacology; Gene Expression Regulation, Enzymologic/drug effects; Gene Expression Regulation, Enzymologic/physiology; Male; Membrane Proteins/metabolism; Mice; Mitochondrial Membranes/enzymology; Mitochondrial Membranes/ultrastructure; Mitochondrial Proteins/metabolism; Organ Specificity/drug effects; Organ Specificity/physiology; Rats; Staurosporine/pharmacology; Substrate Specificity/drug effects; Substrate Specificity/physiology; Testis/enzymology; Testis/ultrastructure

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


See also

References

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