Both Decreased and Increased SRPK1 Levels Promote Cancer by Interfering with PHLPP-Mediated Dephosphorylation of Akt

• DOI: 10.1016/j.molcel.2014.03.007
• Publication Date: 2014-04-03T16:53:50Z
• Authors: Pingping Wang; Zhihong Zhou; Anchang Hu; Claudio Ponte de ...; Yu Zhou; Lixin Hong; Emma Sierecki; Masahiko Ajiro; Michael Kruhlak; Curtis Harris; Kun-Liang Guan; Zhi-Ming Zheng; Alexandra C. Newton; Peiqing Sun; Huilin Zhou; Xiang-Dong Fu
• Keywords: Pleckstrin homology domain; Dephosphorylation; Proto-Oncogene Proteins c-akt; Protein phosphatase 1

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.