a rna interference screen identifies the protein phosphatase 2a subunit pr55γ as a stress-sensitive inhibitor of c-srcrna干扰屏幕识别蛋白磷酸酶2亚基pr55γ物抑制剂的c - src.pdfVIP

A RNA Interference Screen Identifies the Protein Phosphatase 2A Subunit PR55c as a Stress-Sensitive Inhibitor of c-SRC 1 1 2,3 4 ´ 1* Pieter J. A. Eichhorn , Menno P. Creyghton , Kevin Wilhelmsen , Hans van Dam , Rene Bernards 1 Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands, 2 Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands, 3 Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands, 4 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands Protein Phosphatase type 2A (PP2A) represents a family of holoenzyme complexes with diverse biological activities. Specific holoenzyme complexes are thought to be deregulated during oncogenic transformation and oncogene- induced signaling. Since most studies on the role of this phosphatase family have relied on the use of generic PP2A inhibitors, the contribution of individual PP2A holoenzyme complexes in PP2A-controlled signaling pathways is largely unclear. To gain insight into this, we have constructed a set of shRNA vectors targeting the individual PP2A regulatory subunits for suppression by RNA interference. Here, we identify PR55c and PR55d as inhibitors of c-Jun NH2-terminal kinase (JNK) activation by UV irradiation. We show that PR55c binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC. We also find that the physical interaction between PR55c and c-SRC is sensitive to UV irradiation. Our data reveal a novel mechanism of c-SRC regulation whereby in response to stress c-SRC activity is regulated, at least in part, through l