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.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
Pingping
P
Wang
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
Zhihong
Z
Zhou
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
Anchang
A
Hu
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.
Claudio
C
Ponte de Albuquerque
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
Yu
Y
Zhou
Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Lixin
L
Hong
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0651, USA.
Emma
E
Sierecki
Tumor Virus RNA Biology Section, Gene Regulation and Chromosome Biology Laboratory, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
Masahiko
M
Ajiro
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
Michael
M
Kruhlak
Laboratory of Human Carcinogenesis, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
Curtis
C
Harris
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0651, USA.
Kun-Liang
KL
Guan
Tumor Virus RNA Biology Section, Gene Regulation and Chromosome Biology Laboratory, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.
Zhi-Ming
ZM
Zheng
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0651, USA.
Alexandra C
AC
Newton
Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Peiqing
P
Sun
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.
Huilin
H
Zhou
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.
Xiang-Dong
XD
Fu
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D016922:Cellular Senescence; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D047368:Tumor Burden
D009687:Nuclear Proteins; C490215:Srpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C519282:PHLPP1 protein, mouse; D010749:Phosphoprotein Phosphatases