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The PPLA Motif of Glycogen Synthase Kinase 3β Is Required for Interaction with Fe65  

Lee, Eun Jeoung (School of Science Education, Chungbuk National University)
Hyun, Sunghee (Department of Pre-medicine, Eulji University School of Medicine)
Chun, Jaesun (Department of Biology Education, Korea National University of Education)
Shin, Sung Hwa (School of Science Education, Chungbuk National University)
Lee, Kyung Eun (School of Science Education, Chungbuk National University)
Yeon, Kwang Hum (Department of Biology Education, Korea National University of Education)
Park, Tae Yoon (Graduate School of Education, Yonsei University)
Kang, Sang Sun (School of Science Education, Chungbuk National University)
Abstract
Glycogen synthase kinase $3{\beta}$ (GSK $3{\beta}$) is a serine/threonine kinase that phosphorylates substrates such as ${\beta}$-catenin and is involved in a variety of biological processes, including embryonic development, metabolism, tumorigenesis, and cell death. Here, we present evidence that human GSK $3{\beta}$ is associated with Fe65, which has the characteristics of an adaptor protein, possessing a WW domain, and two phosphotyrosine interaction domains, PID1 and PID2. The GSK $3{\beta}$ catalytic domain also contains a putative WW domain binding motif ($^{371}PPLA^{374}$), and we observed, using a pull down approach and co-immunoprecipitation, that it interacts physically with Fe65 via this motif. In addition, we detected co-localization of GSK $3{\beta}$ and Fe65 by confocal microscopy, and this co-localization was disrupted by mutation of the putative WW domain binding motif of GSK $3{\beta}$. Finally, in transient transfection assays interaction of GSK $3{\beta}$ (wt) with Fe65 induced substantial cell apoptosis, whereas interaction with the GSK $3{\beta}$ AALA mutant ($^{371}AALA^{374}$) did not, and we noted that phosphorylation of the Tyr 216 residue of the GSK $3{\beta}$ AALA mutant was significantly reduced compared to that of GSK $3{\beta}$ wild type. Thus, our observations indicate that GSK $3{\beta}$ binds to Fe65 through its $^{371}PPLA^{374}$ motif and that this interaction regulates apoptosis and phosphorylation of Tyr 216 of GSK $3{\beta}$.
Keywords
confocal microscopy; Fe65; GSK $3{\beta}$ protein phosphorylation; protein-protein interaction; subcellular localization;
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