Myristoylation of the Dual Specificity Phosphatase JSP1 is necessary for its Activation of JNK Signaling and Apoptosis

• Published in: The FEBS journal 2010-06, Vol.277 (11), p.2463-2473
• Main Authors: Schwertassek, Ulla, Buckley, Deirdre A., Xu, Chong-Feng, Lindsay, Andrew J., McCaffrey, Mary W., Neubert, Thomas A., Tonks, Nicholas K.
• Format: Article
• Language: English
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2010.07661.x

Activation of the c-JUN N-terminal kinase (JNK) pathway is implicated in a number of important physiological processes, from embryonic morphogenesis to cell survival and apoptosis. JNK stimulatory phosphatase 1 (JSP1) is a member of the dual specificity phosphatase subfamily of protein tyrosine phosphatases (PTPs). In contrast to other dual specificity phosphatases, which catalyze inactivation of mitogen-activated protein kinases, expression of JSP1 activates JNK-mediated signaling. JSP1 (and its relative DUSP15) are unique among members of the PTP family in that they contain a potential myristoylation site at the N-terminus (M G NGMXK). In this study, we investigated whether JSP1 was myristoylated and examined the functional consequences of myristoylation. Using mass spectrometry, we showed that wild type JSP1, but not a JSP1 mutant in which glycine 2 was mutated to alanine (JSP1-G2A), was myristoylated in cells. Abrogation of myristoylation did not impair the intrinsic phosphatase activity of JSP1, but changed the subcellular localization of the enzyme. Compared to wild type, the ability of non-myristoylated JSP1 to induce JNK activation and phosphorylation of the transcription factor c-JUN was attenuated. Upon expression of wild type JSP1, a subpopulation of cells, with highest levels of the phosphatase, was induced to float off the dish and undergo apoptosis. In contrast, cells expressing similar levels of JSP1-G2A remained attached, further highlighting that the myristoylation mutant was functionally compromised.