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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics C Study Section (MGC)
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Bender, Michael T
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University of California San Diego
Other Basic Sciences
Schools of Medicine
La Jolla
United States
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Fu, Xiang-Dong (2017) Both sides of the same coin: Rac1 splicing regulating by EGF signaling. Cell Res 27:455-456
Jiang, Li; Shao, Changwei; Wu, Qi-Jia et al. (2017) NEAT1 scaffolds RNA-binding proteins and the Microprocessor to globally enhance pri-miRNA processing. Nat Struct Mol Biol 24:816-824
Hu, Jing; Sun, Tao; Wang, Hui et al. (2016) MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B. Cancer Cell 29:49-60
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 63:218-228
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
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
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
Han, Yixing; Gao, Shouguo; Muegge, Kathrin et al. (2015) Advanced Applications of RNA Sequencing and Challenges. Bioinform Biol Insights 9:29-46
Fu, Xiang-Dong (2015) Yes, SiR. RNA 21:619-21
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

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