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

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. [Display omitted] •SRPK1 acts as a general signal modulator besides its role in regulated splicing•Both SRPK1 null mutation and overexpression cause constitutive Akt activation•SRPK1 mediates the recruitment of the phosphatase PHLPP1 to Akt•SRPK1 may contribute to tumorigenesis as an oncogene or tumor suppressor SRPK1 is a downstream target of Akt. Wang et al. find that SRPK1, in turn, regulates Akt by recruiting the phosphatase PHLPP1 to Akt. Interestingly, both decreased and increased SRPK1 levels cause Akt activation and transformation—loss of SRPK1 prevents PHLPP1 recruitment, and SRPK1 overexpression titrates PHLPP away from Akt.