Format

Send to

Choose Destination
See comment in PubMed Commons below
Mol Cell. 2014 May 8;54(3):378-91. doi: 10.1016/j.molcel.2014.03.007. Epub 2014 Apr 3.

Both decreased and increased SRPK1 levels promote cancer by interfering with PHLPP-mediated dephosphorylation of Akt.

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0651, USA.
3
Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
4
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0651, USA.
5
Tumor Virus RNA Biology Section, Gene Regulation and Chromosome Biology Laboratory, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
6
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
7
Laboratory of Human Carcinogenesis, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
8
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA. Electronic address: xdfu@ucsd.edu.

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.

PMID:
24703948
PMCID:
PMC4019712
DOI:
10.1016/j.molcel.2014.03.007
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center