Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines

Alessi, Dario R.; Gómez, Néstor; Moorhead, Greg B. G.; Lewis, Tom; Keyse, Stephen M.; Cohen, Philip

doi:10.1016/s0960-9822(95)00059-5

Cited by 343 publications

(296 citation statements)

References 40 publications

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“…ERKs are activated by phosphorylation of both conserved threonine and tyrosine residues and inactivated on dephosphorylation by specific phosphatases (15)(16)(17)(18)(19)(20). Serine-threonine PP2A can dephosphorylate MEKand ERK-family kinases in vitro (21,22).…”

Section: Discussionmentioning

confidence: 99%

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

Yoon

Kim

Park

et al. 2009

Molecular Cancer Research

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Sphingosine induces activation of multiple signaling pathways that play critical roles in controlling cell death. However, the precise molecular mechanism of cell death induced by sphingosine remains to be clarified. In this study, we show that sphingosine induces death receptor -independent caspase-8 activation and apoptotic cell death via p38 mitogen-activated protein kinase (MAPK) activation and that suppression of the MAPK/extracellular signal -regulated kinase (ERK) kinase/ERK pathway by protein phosphatase 2A (PP2A) is required for p38 MAPK activation. Treatment of cells with sphingosine induced suppression of ERK and activation of p38 MAPK. Inhibition of p38 MAPK led to the marked suppression of death receptor -independent caspase-8 activation and subsequent cell death induced by sphingosine. Interestingly, pretreatment with phorbol 12-myristate 13-acetate or transfection of MAPK/ERK kinase/ERK resulting in ERK activation completely attenuated sphingosine-induced p38 MAPK activation. PP2A activity was additionally elevated on sphingosine treatment. Small interfering RNA targeting of PP2A effectively attenuated sphingosine-induced p38 MAPK activation through restoration of ERK activity, suggesting PP2A-mediated opposing regulation of ERK and p38 MAPK. Our findings clearly imply that activation of p38 MAPK promotes death receptor -independent activation of caspase-8 and apoptotic cell death pathways, thus providing a novel cellular mechanism for the anticancer activity of sphingolipid metabolites.

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Section: Discussionmentioning

confidence: 99%

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

Yoon

Kim

Park

et al. 2009

Molecular Cancer Research

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“…MKP-1 and CL100 were originally identi®ed as ERK speci®c phosphatases, capable of dephosphorylating this MAPK (Sun et al, 1993;Alessi et al, 1993). However, in some mammalian cell lines the inactivation of this MAPK is too fast to indicate an involvement of CL100 in this process, and other phosphatases appear to be involved in the inactivation of MAPK (Alessi et al, 1995;Wu et al, 1994). Recent work has also implicated MKP-1 in the inactivation of the other members of the MAPK family, namely JNK and p38 in di erent model systems (Gupta et al, 1996;Chu et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential

et al. 2002

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Although early stage ovarian cancer can be e ectively treated with surgery and chemotherapy, the majority of cases present with advanced disease, which remains essentially incurable. Unfortunately, little is known about the genes important for the development and progression of this disease. In this study, the expression of 68 phosphatases was determined in immortalized ovarian epithelial cells (IOSE) and compared to ovarian cancer cell lines. CL100, a dual speci®city phosphatase, displayed 10 ± 25-fold higher expression in normal compared to malignant ovarian cell lines. Immunohistochemical staining of normal ovaries and 68 ovarian cancer specimens con®rmed this di erential expression. Re-expression of CL100 in ovarian cancer cells decreased adherent and nonadherent cell growth and induced phenotypic changes including loss of ®lopodia and lamellipodia with an associated decrease in cell motility. Induced expression of CL100 in ovarian cancer cells suppressed intraperitoneal tumor growth in nude mice. These results show for the ®rst time that CL100 expression is altered in human ovarian cancer, that CL100 expression changes cell morphology and motility, and that it suppresses intraperitoneal growth of human ovarian epithelial cancer. These data suggest that down-regulation of CL100 may play a role in the progression of human ovarian cancer.

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“…Dual specificity phosphatases in vertebrates and S. cerevisiae inactivate MAPKs in vitro and in vivo. The vertebrate MKP-1 inactivates ERK1 and ERK2 in vitro, but it is not certain this occurs in vivo (11)(12)(13)(14). The yeast Msg5 inactivates Fus3 in vitro and in vivo (15).…”

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confidence: 99%

“…Cells treated with okadaic acid, an inhibitor of PP2A, activate MAPK in vivo (17). Since okadaic acid also activates MEK, it is not clear that PP2A inactivates MAPK in vivo (13,17,18). Two protein-tyrosine phosphatases, Pyp1 and Pyp2 in Schizosaccharomyces pombe, inactivate Sty1/ Spc1 in vitro and in vivo (19 -21).…”

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confidence: 99%

Two Protein-tyrosine Phosphatases Inactivate the Osmotic Stress Response Pathway in Yeast by Targeting the Mitogen-activated Protein Kinase, Hog1

Jacoby

Flanagan

Faykin

et al. 1997

Journal of Biological Chemistry

154

209

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. In S. cerevisiae, a putative protein-tyrosine phosphatase encoded by PTP2 (22-24) negatively regulates the osmotic stress response pathway, and indirect evidence suggests this occurs by dephosphorylation of Hog1-phosphotyrosine (Hog1-Tyr(P)) (25).We sought to examine further the regulation of MAPK pathways by identifying and characterizing protein phosphatases that act on the HOG pathway in S. cerevisiae. This pathway allows yeast to grow in high osmolarity environments by inducing the expression of osmoprotectants via activation of the MAPK module, Pbs2-Hog1 (Fig. 1) (26). Upstream of the MAPK module is a negative regulator, the "two-component system," comprised of three sequentially acting kinases including Sln1, a plasma membrane bound histidine/aspartyl kinase, Ypd1, a histidine kinase, and Ssk1, an aspartyl kinase (25,27,28). These kinases negatively regulate two MEKKs called Ssk2 and Ssk22 (29). There is also a positive regulator upstream of the MAPK module called Sho1 which activates Pbs2 directly (29). The model for activation of this pathway is as follows. Osmotic

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Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines

Cited by 343 publications

References 40 publications

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential

Two Protein-tyrosine Phosphatases Inactivate the Osmotic Stress Response Pathway in Yeast by Targeting the Mitogen-activated Protein Kinase, Hog1

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