1. Both Decreased and Increased SRPK1 Levels Promote Cancer by Interfering with PHLPP-Mediated Dephosphorylation of Akt
- Author
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Wang, Pingping, Zhou, Zhihong, Hu, Anchang, de Albuquerque, Claudio Ponte, Zhou, Yu, Hong, Lixin, Sierecki, Emma, Ajiro, Masahiko, Kruhlak, Michael, Harris, Curtis, Guan, Kun-Liang, Zheng, Zhi-Ming, Newton, Alexandra C, Sun, Peiqing, Zhou, Huilin, and Fu, Xiang-Dong
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Genetics ,Cancer ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Underpinning research ,Aetiology ,Animals ,Carcinogenesis ,Cell Adhesion ,Cells ,Cultured ,Cellular Senescence ,Colonic Neoplasms ,Enzyme Activation ,Female ,Humans ,Male ,Mice ,Mice ,129 Strain ,Mice ,Knockout ,Mice ,Nude ,Neoplasm Transplantation ,Nuclear Proteins ,Phosphoprotein Phosphatases ,Phosphorylation ,Protein Processing ,Post-Translational ,Protein Serine-Threonine Kinases ,Proto-Oncogene Proteins c-akt ,Tumor Burden ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Akt activation is a hallmark of human cancers. Here, we report a critical mechanism for regulation of Akt activity by the splicing kinase SRPK1, a downstream Akt target for transducing growth signals to regulate splicing. Surprisingly, we find that SRPK1 has a tumor suppressor function because ablation of SRPK1 in mouse embryonic fibroblasts induces cell transformation. We link the phenotype to constitutive Akt activation from genome-wide phosphoproteomics analysis and discover that downregulated SRPK1 impairs the recruitment of the Akt phosphatase PHLPP1 (pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase) to Akt. Interestingly, SRPK1 overexpression is also tumorigenic because excess SRPK1 squelches PHLPP1. Thus, aberrant SRPK1 expression in either direction induces constitutive Akt activation, providing a mechanistic basis for previous observations that SRPK1 is downregulated in some cancer contexts and upregulated in others.
- Published
- 2014