This project focuses on SRPK1 and SRPK2, major kinases responsible for the phosphorylation of SR proteins and RS domain-containing splicing factors and regulators in mammalian cells. We demonstrated that both of these splicing kinases are anchored in the cytoplasm through interactions with molecular chaperons and that they can be induced to translocate to the nucleus in response to cellular signaling. We recently discovered that these kinases are direct substrates of activated Akt, representing a new branch of the EGF pathway to regulate SR protein phosphorylation and alternative splicing in the nucleus. Interestingly, these splicing kinases also modulate the functional state of Akt via a novel feedback mechanism, and as a functional consequence, we found that depletion of SRPK1 is sufficient to transform immobilized MEFs. Based on these recent findings, we now propose three specific aims to (1) define SRPKs as signal transducers for regulated splicing using global approaches in combination with biochemical dissection of key signal transduction pathways involved, (2) elucidate the mechanism underlying SRPK-mediated signaling by characterizing specific molecular switches induced by upstream signaling events, and (3) determine the function and regulatory role of SRPKs in tumorigenesis by pursuing the hypotheses that SRPKs may regulate Akt and synergize with other key regulators in the Akt pathway to determine cell fate and promote tumorigenesis. The proposed studies are expected to have broad implications on regulated splicing, signal transduction and cancer biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052872-15
Application #
8602835
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Bender, Michael T
Project Start
1996-05-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
15
Fiscal Year
2014
Total Cost
$295,793
Indirect Cost
$104,959
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Zhang, Xiaorong; Zuo, Xinxin; Yang, Bo et al. (2014) MicroRNA directly enhances mitochondrial translation during muscle differentiation. Cell 158:607-19
Wang, Pingping; Zhou, Zhihong; Hu, Anchang et al. (2014) Both decreased and increased SRPK1 levels promote cancer by interfering with PHLPP-mediated dephosphorylation of Akt. Mol Cell 54:378-91
Fu, Xiang-Dong; Ares Jr, Manuel (2014) Context-dependent control of alternative splicing by RNA-binding proteins. Nat Rev Genet 15:689-701
Pandit, Shatakshi; Zhou, Yu; Shiue, Lily et al. (2013) Genome-wide analysis reveals SR protein cooperation and competition in regulated splicing. Mol Cell 50:223-35
Ji, Xiong; Zhou, Yu; Pandit, Shatakshi et al. (2013) SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell 153:855-68
Wang, Yanling; Jiang, Li; Ji, Xiong et al. (2013) Hepatitis B viral RNA directly mediates down-regulation of the tumor suppressor microRNA miR-15a/miR-16-1 in hepatocytes. J Biol Chem 288:18484-93
Xue, Yuanchao; Ouyang, Kunfu; Huang, Jie et al. (2013) Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell 152:82-96
Zhou, Zhihong; Fu, Xiang-Dong (2013) Regulation of splicing by SR proteins and SR protein-specific kinases. Chromosoma 122:191-207
Xiao, Rui; Tang, Peng; Yang, Bo et al. (2012) Nuclear matrix factor hnRNP U/SAF-A exerts a global control of alternative splicing by regulating U2 snRNP maturation. Mol Cell 45:656-68
Han, Joonhee; Xiong, Ji; Wang, Dong et al. (2011) Pre-mRNA splicing: where and when in the nucleus. Trends Cell Biol 21:336-43

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