Type-2A protein phosphatase activity is required to maintain death receptor responsiveness

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Härmälä-Brasken AS, Mikhailov A, Söderström TS, Meinander A, Holmström TH, Damuni Z, Eriksson JE
Publication year: 2003
Journal: Oncogene
Journal acronym: ONCOGENE
Volume number: 22
Issue number: 48
Start page: 7677
End page: 7686
Number of pages: 10
ISSN: 0950-9232
eISSN: 1476-5594


Abstract

Type-2A protein phosphatase (PP2A) is a key regulator in many different cell signaling pathways and an important determinant in tumorigenesis. One of the signaling targets of PP2A is the mitogen-activated protein kinase (MAPK/ ERK) cascade. In this study, we wanted to determine whether PP2A could be involved in regulation of death receptor activity through its capacity to regulate MAPK/ ERK. To this end, we studied the effects of two different routes of protein phosphatase inhibition on death receptor-mediated apoptosis. We demonstrated that the apoptosis mediated by Fas, TNF-alpha, and TRAIL in U937 cells is suppressed by calyculin A, an inhibitor of type-1 and type-2A protein phosphatases. The inhibition of the protein phosphatase activity was shown to subsequently increase the MAPK activity in these cells, and the level of activation corresponded to the degree of suppression of cytokine-mediated apoptosis. A more physiological inhibitor, the intracellular PP2A inhibitor protein I-2(PP2A), protected transfected HeLa cells in a similar way from Fas-mediated apoptosis and induced activation of MAPK in I-2(PP2A) transfected cells. A corresponding inhibition could also be obtained by stable transfection with a constitutively active form of the MAPK kinase, MKK1 (also referred to as MEK1). The inhibitor-mediated protection was highly efficient in preventing early stages of apoptosis, as no caspase-8 cleavage occurred in these cells. The observed apoptosis suppression is likely to facilitate the tumor-promoting effect of a range of different type-2A protein phosphatase inhibitors, and could explain the reported tumor association of I-2(PP2A).


Keywords

calyculin A, I-2(PP2A), inhibition, PP2A, receptor-induced apoptosis

Last updated on 2019-13-11 at 05:27