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
Aubol, Brandon E; Wu, Guowei; Keshwani, Malik M et al. (2016) Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing. Mol Cell 63:218-28
Keshwani, Malik M; Aubol, Brandon E; Fattet, Laurent et al. (2015) Conserved proline-directed phosphorylation regulates SR protein conformation and splicing function. Biochem J 466:311-22
Zhang, Peng; Kang, Jun-Yan; Gou, Lan-Tao et al. (2015) MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes. Cell Res 25:193-207
Mallory, Michael J; Allon, Samuel J; Qiu, Jinsong et al. (2015) Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling. Proc Natl Acad Sci U S A 112:E2139-48
Wang, Lanfeng; Zhou, Yu; Xu, Liang et al. (2015) Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex. Nature 523:621-5
Fu, Xiang-Dong (2015) Yes, SiR. RNA 21:619-21
Martinez, Nicole M; Agosto, Laura; Qiu, Jinsong et al. (2015) Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation. Genes Dev 29:2054-66
Han, Yixing; Gao, Shouguo; Muegge, Kathrin et al. (2015) Advanced Applications of RNA Sequencing and Challenges. Bioinform Biol Insights 9:29-46
Cai, Zhiqiang; Cao, Ran; Zhang, Kai et al. (2015) Oncogenic miR-17/20a Forms a Positive Feed-forward Loop with the p53 Kinase DAPK3 to Promote Tumorigenesis. J Biol Chem 290:19967-75
Zhang, Xiaorong; Zuo, Xinxin; Yang, Bo et al. (2014) MicroRNA directly enhances mitochondrial translation during muscle differentiation. Cell 158:607-19

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