Glycogen synthase kinase‐3 and alternative splicing

Advanced Review

Xiaolei Liu, Peter S. Klein

Published Online: Aug 17 2018

DOI: 10.1002/wrna.1501

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Glycogen synthase kinase‐3 (GSK‐3) is a highly conserved negative regulator of receptor tyrosine kinase, cytokine, and Wnt signaling pathways. Stimulation of these pathways inhibits GSK‐3 to modulate diverse downstream effectors that include transcription factors, nutrient sensors, glycogen synthesis, mitochondrial function, circadian rhythm, and cell fate. GSK‐3 also regulates alternative splicing in response to T‐cell receptor activation, and recent phosphoproteomic studies have revealed that multiple splicing factors and regulators of RNA biosynthesis are phosphorylated in a GSK‐3‐dependent manner. Furthermore, inhibition of GSK‐3 alters the splicing of hundreds of mRNAs, indicating a broad role for GSK‐3 in the regulation of RNA processing. GSK‐3‐regulated phosphoproteins include SF3B1, SRSF2, PSF, RBM8A, nucleophosmin 1 (NPM1), and PHF6, many of which are mutated in leukemia and myelodysplasia. As GSK‐3 is inhibited by pathways that are pathologically activated in leukemia and loss of Gsk3 in hematopoietic cells causes a severe myelodysplastic neoplasm in mice, these findings strongly implicate GSK‐3 as a critical regulator of mRNA processing in normal and malignant hematopoiesis. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

Glycogen synthase kinase‐3 (GSK‐3) regulated signaling pathways and splicing factor phosphorylation. Antigen stimulation of the T‐cell receptor (TCR) activates the cytosolic protein kinase AKT, which inhibits GSK‐3 by phosphorylation at a conserved N‐terminal serine. Inhibition of GSK‐3 allows the polypyrimidine tract‐binding protein (PTB)‐associated splicing factor (PSF) to modulate the splicing of CD45 pre‐mRNA, as described in detail in Figure (Heyd & Lynch, ). Growth factor signaling through receptor tyrosine kinases (RTKs) also activates AKT and inhibits GSK‐3, allowing activation of diverse downstream effectors, including glycogen synthase. (Both Akt and GSK‐3 have multiple targets not shown here for the sake of clarity.) This pathway could also modulate GSK‐3‐dependent phosphorylation of splicing factors in the cytosol or within the nucleus (Hartmann et al., ). The Wnt pathway is also suppressed by GSK‐3. In the absence of Wnts, GSK‐3 phosphorylates β‐catenin, promoting its proteosomal degradation. Wnt signaling inhibits GSK‐3 through a distinct, AKT‐independent mechanism, stabilizing β‐catenin, which then activates Wnt target gene expression. Wnts could also regulate splicing factor phosphorylation through inhibition of GSK‐3 as well as through other downstream effectors of Wnt signaling (Goncalves, Matos, & Jordan, ; Hartmann et al., )

[ Normal View | Magnified View ]

Glycogen synthase kinase‐3 (GSK‐3) phosphorylation of RS motif. GSK‐3‐dependent phosphorylation of serine–arginine (SR)‐rich splicing factors identified by SILAC/MS comparing wild‐type and Gsk3 KO mouse embryonic stem cells (Shinde et al., ). Phosphorylated residues are in red. RS motif is in bold

[ Normal View | Magnified View ]

Role of glycogen synthase kinase‐3 (GSK‐3) in TCR regulation of CD45 splicing. CD45 encodes a receptor tyrosine phosphatase that serves as a feedback inhibitor of TCR signaling. In the absence of TCR activation, GSK‐3 phosphorylates PSF, which is sequestered by the thyroid hormone receptor associated protein (TRAP)‐150. Under these conditions, the variable exons 4, 5, and 6 are retained (R456), extending the sequence and reducing the activity of CD45 (only exons 3–7 are shown here). Upon antigen engagement of the TCR, GSK‐3 is phosphorylated and inhibited; newly translated PSF binds to exonic splicing silencer (ESS) elements in exons 4, 5, and 6 of the CD45 pre‐mRNA and promotes exon exclusion, leading to expression of a more active PTPase (Heyd & Lynch, , ). Multiple splice variants are expressed; for clarity only the R0 form, lacking all three variable exons, is shown

[ Normal View | Magnified View ]

References

Abrahamsson,, A. E., Geron,, I., Gotlib,, J., Dao,, K. H., Barroga,, C. F., Newton,, I. G., … Jamieson,, C. H. (2009). Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proceedings of the National Academy of Sciences of the United States of America, 106(10), 3925–3929. https://doi.org/10.1073/pnas.0900189106
Alt,, J. R., Cleveland,, J. L., Hannink,, M., & Diehl,, J. A. (2000). Phosphorylation‐dependent regulation of cyclin D1 nuclear export and cyclin D1‐dependent cellular transformation. Genes %26 Development, 14(24), 3102–3114.
Araki,, S., Dairiki,, R., Nakayama,, Y., Murai,, A., Miyashita,, R., Iwatani,, M., … Nakanishi,, O. (2015). Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre‐mRNA splicing. PLoS One, 10(1), e0116929. https://doi.org/10.1371/journal.pone.0116929
Azoulay‐Alfaguter,, I., Yaffe,, Y., Licht‐Murava,, A., Urbanska,, M., Jaworski,, J., Pietrokovski,, S., … Eldar‐Finkelman,, H. (2011). Distinct molecular regulation of glycogen synthase kinase‐3alpha isozyme controlled by its N‐terminal region: Functional role in calcium/calpain signaling. Journal of Biological Chemistry, 286(15), 13470–13480. https://doi.org/10.1074/jbc.M110.127969
Banerji,, V., Frumm,, S. M., Ross,, K. N., Li,, L. S., Schinzel,, A. C., Hahn,, C. K., … Stegmaier,, K. (2012). The intersection of genetic and chemical genomic screens identifies GSK‐3alpha as a target in human acute myeloid leukemia. Journal of Clinical Investigation, 122(3), 935–947. https://doi.org/10.1172/JCI46465
Barrell,, W. B., Szabo‐Rogers,, H. L., & Liu,, K. J. (2012). Novel reporter alleles of GSK‐3alpha and GSK‐3beta. PLoS One, 7(11), e50422. https://doi.org/10.1371/journal.pone.0050422
Beals,, C. R., Sheridan,, C. M., Turck,, C. W., Gardner,, P., & Crabtree,, G. R. (1997). Nuclear export of NF‐ATc enhanced by glycogen synthase kinase‐3. Science, 275(5308), 1930–1934.
Beurel,, E., Grieco,, S. F., & Jope,, R. S. (2015). Glycogen synthase kinase‐3 (GSK3): Regulation, actions, and diseases. Pharmacology %26 Therapeutics, 148, 114–131. https://doi.org/10.1016/j.pharmthera.2014.11.016
Beurel,, E., & Jope,, R. S. (2006). The paradoxical pro‐ and anti‐apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Progress in Neurobiology, 79(4), 173–189. https://doi.org/10.1016/j.pneurobio.2006.07.006
Bhavanasi,, D., Wen,, K. W., Liu,, X., Vergez,, F., Danet‐Desnoyers,, G., Carroll,, M., … Klein,, P. S. (2017). Signaling mechanisms that regulate ex vivo survival of human acute myeloid leukemia initiating cells. Blood Cancer Journal, 7(12), 636. https://doi.org/10.1038/s41408-017-0003-1
Bijur,, G. N., De Sarno,, P., & Jope,, R. S. (2000). Glycogen synthase kinase‐3beta facilitates staurosporine‐ and heat shock‐induced apoptosis. Protection by lithium. Journal of Biological Chemistry, 275(11), 7583–7590.
Bijur,, G. N., & Jope,, R. S. (2001). Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase‐3 beta. Journal of Biological Chemistry, 276(40), 37436–37442. https://doi.org/10.1074/jbc.M105725200
Blaustein,, M., Pelisch,, F., Tanos,, T., Munoz,, M. J., Wengier,, D., Quadrana,, L., … Srebrow,, A. (2005). Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT. Nature Structural %26 Molecular Biology, 12(12), 1037–1044. https://doi.org/10.1038/nsmb1020
Bordonaro,, M. (2013). Crosstalk between Wnt signaling and RNA processing in colorectal cancer. Journal of Cancer, 4(2), 96–103. https://doi.org/10.7150/jca.5470
Boudrez,, A., Beullens,, M., Waelkens,, E., Stalmans,, W., & Bollen,, M. (2002). Phosphorylation‐dependent interaction between the splicing factors SAP155 and NIPP1. Journal of Biological Chemistry, 277(35), 31834–31841. https://doi.org/10.1074/jbc.M204427200
Box,, J. K., Paquet,, N., Adams,, M. N., Boucher,, D., Bolderson,, E., O`Byrne,, K. J., & Richard,, D. J. (2016). Nucleophosmin: From structure and function to disease development. BMC Molecular Biology, 17(1), 19. https://doi.org/10.1186/s12867-016-0073-9
Busch,, A., & Hertel,, K. J. (2012). Evolution of SR protein and hnRNP splicing regulatory factors. WIREs RNA, 3(1), 1–12. https://doi.org/10.1002/wrna.100
Cancer Genome Atlas Research Network. (2013). Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. New England Journal of Medicine, 368(22), 2059–2074. https://doi.org/10.1056/NEJMoa1301689
Chen,, L., Kostadima,, M., Martens,, J. H., Canu,, G., Garcia,, S. P., Turro,, E., … Rendon,, A. (2014). Transcriptional diversity during lineage commitment of human blood progenitors. Science, 345(6204), 1251033. https://doi.org/10.1126/science.1251033
Chen,, X., Wang,, R., Liu,, X., Wu,, Y., Zhou,, T., Yang,, Y., … Ying,, Q. L. (2017). A chemical‐genetic approach reveals the distinct roles of GSK3alpha and GSK3beta in regulating embryonic stem cell fate. Developmental Cell, 43(5), 563–576 e564. https://doi.org/10.1016/j.devcel.2017.11.007
Chuang,, T. W., Lee,, K. M., & Tarn,, W. Y. (2015). Function and pathological implications of exon junction complex factor Y14. Biomolecules, 5(2), 343–355. https://doi.org/10.3390/biom5020343
Covelo‐Molares,, H., Bartosovic,, M., & Vanacova,, S. (2018). RNA methylation in nuclear pre‐mRNA processing. WIREs RNA, e1489. https://doi.org/10.1002/wrna.1489
Cross,, D., Alessi,, D., Cohen,, P., Andjelkovich,, M., & Hemmings,, B. (1995). Inhibition of glycogen synthase kinase‐3 by insulin mediated by protein kinase B. Nature, 378, 785–789.
Ding,, V. W., Chen,, R. H., & McCormick,, F. (2000). Differential regulation of glycogen synthase kinase 3beta by insulin and Wnt signaling. Journal of Biological Chemistry, 275(42), 32475–32481.
Doble,, B. W., Patel,, S., Wood,, G. A., Kockeritz,, L. K., & Woodgett,, J. R. (2007). Functional redundancy of GSK‐3alpha and GSK‐3beta in Wnt/beta‐catenin signaling shown by using an allelic series of embryonic stem cell lines. Developmental Cell, 12(6), 957–971.
Doble,, B. W., & Woodgett,, J. R. (2003). GSK‐3: Tricks of the trade for a multi‐tasking kinase. Journal of Cell Science, 116(Pt. 7), 1175–1186.
Dolatshad,, H., Pellagatti,, A., Fernandez‐Mercado,, M., Yip,, B. H., Malcovati,, L., Attwood,, M., … Boultwood,, J. (2015). Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia, 29(5), 1092–1103. https://doi.org/10.1038/leu.2014.331
Dvinge,, H., Kim,, E., Abdel‐Wahab,, O., & Bradley,, R. K. (2016). RNA splicing factors as oncoproteins and tumour suppressors. Nature Reviews. Cancer, 16(7), 413–430. https://doi.org/10.1038/nrc.2016.51
Edmond,, V., Moysan,, E., Khochbin,, S., Matthias,, P., Brambilla,, C., Brambilla,, E., … Eymin,, B. (2011). Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin. EMBO Journal, 30(3), 510–523. https://doi.org/10.1038/emboj.2010.333
Edwards,, C. R., Ritchie,, W., Wong,, J. J., Schmitz,, U., Middleton,, R., An,, X., … Blobel,, G. A. (2016). A dynamic intron retention program in the mammalian megakaryocyte and erythrocyte lineages. Blood, 127, e24–e34. https://doi.org/10.1182/blood-2016-01-692764
Eto,, K., Sonoda,, Y., & Abe,, S. (2011). The kinase DYRKIA regulates pre‐mRNA splicing in spermatogonia and proliferation of spermatogonia and Sertoli cells by phosphorylating a spliceosomal component, SAP155, in postnatal murine testes. Molecular and Cellular Biochemistry, 355(1–2), 217–222. https://doi.org/10.1007/s11010-011-0857-7
Falini,, B., Mecucci,, C., Tiacci,, E., Alcalay,, M., Rosati,, R., Pasqualucci,, L., … Party,, G. A. L. W. (2005). Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. New England Journal of Medicine, 352(3), 254–266. https://doi.org/10.1056/NEJMoa041974
Faulds,, K. J., Egelston,, J. N., Sedivy,, L. J., Mitchell,, M. K., Garimella,, S., Kozlowski,, H., … Phiel,, C. J. (2018). Glycogen synthase kinase‐3 (Gsk‐3) activity regulates mRNA methylation in mouse embryonic stem cells. Journal of Biological Chemistry, 293, 10731–10743. https://doi.org/10.1074/jbc.RA117.001298
Fiol,, C. J., Mahrenholz,, A. M., Wang,, Y., Roeske,, R. W., & Roach,, P. J. (1987). Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3. Journal of Biological Chemistry, 262(29), 14042–14048.
Focosi,, D., Azzara,, A., Kast,, R. E., Carulli,, G., & Petrini,, M. (2009). Lithium and hematology: Established and proposed uses. Journal of Leukocyte Biology, 85(1), 20–28.
Frame,, S., Cohen,, P., & Biondi,, R. M. (2001). A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Molecular Cell, 7(6), 1321–1327.
Fu,, X. D., & Ares,, M., Jr. (2014). Context‐dependent control of alternative splicing by RNA‐binding proteins. Nature Reviews. Genetics, 15(10), 689–701. https://doi.org/10.1038/nrg3778
Gelsi‐Boyer,, V., Trouplin,, V., Adelaide,, J., Bonansea,, J., Cervera,, N., Carbuccia,, N., … Birnbaum,, D. (2009). Mutations of polycomb‐associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. British Journal of Haematology, 145(6), 788–800. https://doi.org/10.1111/j.1365-2141.2009.07697.x
Giannakouros,, T., Nikolakaki,, E., Mylonis,, I., & Georgatsou,, E. (2011). Serine‐arginine protein kinases: A small protein kinase family with a large cellular presence. FEBS Journal, 278(4), 570–586. https://doi.org/10.1111/j.1742-4658.2010.07987.x
Goncalves,, V., Henriques,, A. F., Pereira,, J. F., Neves Costa,, A., Moyer,, M. P., Moita,, L. F., … Jordan,, P. (2014). Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor‐related Rac1b in colorectal cells. RNA, 20(4), 474–482. https://doi.org/10.1261/rna.041376.113
Goncalves,, V., Matos,, P., & Jordan,, P. (2008). The beta‐catenin/TCF4 pathway modifies alternative splicing through modulation of SRp20 expression. RNA, 14(12), 2538–2549. https://doi.org/10.1261/rna.1253408
Goncalves,, V., Pereira,, J. F. S., & Jordan,, P. (2017). Signaling pathways driving aberrant splicing in cancer cells. Genes (Basel), 9(1), 1–17. https://doi.org/10.3390/genes9010009
Guezguez,, B., Almakadi,, M., Benoit,, Y. D., Shapovalova,, Z., Rahmig,, S., Fiebig‐Comyn,, A., … Bhatia,, M. (2016). GSK3 deficiencies in hematopoietic stem cells initiate pre‐neoplastic state that is predictive of clinical outcomes of human acute leukemia. Cancer Cell, 29(1), 61–74. https://doi.org/10.1016/j.ccell.2015.11.012
Hartmann,, B., Castelo,, R., Blanchette,, M., Boue,, S., Rio,, D. C., & Valcarcel,, J. (2009). Global analysis of alternative splicing regulation by insulin and wingless signaling in Drosophila cells. Genome Biology, 10(1), R11. https://doi.org/10.1186/gb-2009-10-1-r11
Heidel,, F. H., Bullinger,, L., Feng,, Z., Wang,, Z., Neff,, T. A., Stein,, L., … Armstrong,, S. A. (2012). Genetic and pharmacologic inhibition of beta‐catenin targets imatinib‐resistant leukemia stem cells in CML. Cell Stem Cell, 10(4), 412–424. https://doi.org/10.1016/j.stem.2012.02.017
Hermiston,, M. L., Xu,, Z., Majeti,, R., & Weiss,, A. (2002). Reciprocal regulation of lymphocyte activation by tyrosine kinases and phosphatases. Journal of Clinical Investigation, 109(1), 9–14. https://doi.org/10.1172/JCI14794
Hernandez,, F., Perez,, M., Lucas,, J. J., Mata,, A. M., Bhat,, R., & Avila,, J. (2004). Glycogen synthase kinase‐3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer`s disease. Journal of Biological Chemistry, 279(5), 3801–3806. https://doi.org/10.1074/jbc.M311512200
Heyd,, F., & Lynch,, K. W. (2010). Phosphorylation‐dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Molecular Cell, 40(1), 126–137. https://doi.org/10.1016/j.molcel.2010.09.013
Heyd,, F., & Lynch,, K. W. (2011). Degrade, move, regroup: Signaling control of splicing proteins. Trends in Biochemical Sciences, 36(8), 397–404. https://doi.org/10.1016/j.tibs.2011.04.003
Hoeflich,, K. P., Luo,, J., Rubie,, E. A., Tsao,, M. S., Jin,, O., & Woodgett,, J. R. (2000). Requirement for glycogen synthase kinase‐3beta in cell survival and NF‐kappaB activation. Nature, 406(6791), 86–90.
Hsu,, L.‐W., Hsu,, M., Li,, C., Chuang,, T. W., Lin,, R. I., & Tarn,, W. Y. (2005). Phosphorylation of Y14 modulates its interaction with proteins involved in mRNA metabolism and influences its methylation. Journal of Biological Chemistry, 280(41), 34507–34512. https://doi.org/10.1074/jbc.M507658200
Huang,, J., Zhang,, Y., Bersenev,, A., O`Brien,, W. T., Tong,, W., Emerson,, S. G., & Klein,, P. S. (2009). Pivotal role for glycogen synthase kinase‐3 in hematopoietic stem cell homeostasis in mice. Journal of Clinical Investigation, 119(12), 3519–3529. https://doi.org/10.1172/JCI40572
Inoki,, K., Ouyang,, H., Zhu,, T., Lindvall,, C., Wang,, Y., Zhang,, X., … Guan,, K. L. (2006). TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell, 126, 955–968.
Inoue,, D., Bradley,, R. K., & Abdel‐Wahab,, O. (2016). Spliceosomal gene mutations in myelodysplasia: Molecular links to clonal abnormalities of hematopoiesis. Genes %26 Development, 30(9), 989–1001. https://doi.org/10.1101/gad.278424.116
Ishigaki,, Y., Nakamura,, Y., Tatsuno,, T., Ma,, S., & Tomosugi,, N. (2015). Phosphorylation status of human RNA‐binding protein 8A in cells and its inhibitory regulation by Magoh. Experimental Biology and Medicine (Maywood, N.J.), 240(4), 438–445. https://doi.org/10.1177/1535370214556945
Jamieson,, C. H., Ailles,, L. E., Dylla,, S. J., Muijtjens,, M., Jones,, C., Zehnder,, J. L., … Weissman,, I. L. (2004). Granulocyte‐macrophage progenitors as candidate leukemic stem cells in blast‐crisis CML. New England Journal of Medicine, 351(7), 657–667. https://doi.org/10.1056/NEJMoa040258
Jenkins,, J. L., & Kielkopf,, C. L. (2017). Splicing factor mutations in myelodysplasias: Insights from spliceosome structures. Trends in Genetics, 33(5), 336–348. https://doi.org/10.1016/j.tig.2017.03.001
Jiang,, J., & Griffin,, J. D. (2010). Wnt/beta‐catenin pathway modulates the sensitivity of the mutant FLT3 receptor kinase inhibitors in a GSK‐3beta dependent manner. Genes %26 Cancer, 1(2), 164–176. https://doi.org/10.1177/1947601910362446
Kaidanovich‐Beilin,, O., & Woodgett,, J. R. (2011). GSK‐3: Functional insights from cell biology and animal models. Frontiers in Molecular Neuroscience, 4, 40. https://doi.org/10.3389/fnmol.2011.00040
Kandoth,, C., McLellan,, M. D., Vandin,, F., Ye,, K., Niu,, B., Lu,, C., … Ding,, L. (2013). Mutational landscape and significance across 12 major cancer types. Nature, 502(7471), 333–339. https://doi.org/10.1038/nature12634
Katzenberger,, R. J., Marengo,, M. S., & Wassarman,, D. A. (2009). Control of alternative splicing by signal‐dependent degradation of splicing‐regulatory proteins. Journal of Biological Chemistry, 284(16), 10737–10746. https://doi.org/10.1074/jbc.M809506200
Kim,, E., Ilagan,, J. O., Liang,, Y., Daubner,, G. M., Lee,, S. C., Ramakrishnan,, A., … Abdel‐Wahab,, O. (2015). SRSF2 mutations contribute to myelodysplasia by mutant‐specific effects on exon recognition. Cancer Cell, 27(5), 617–630. https://doi.org/10.1016/j.ccell.2015.04.006
Komeno,, Y., Yan,, M., Matsuura,, S., Lam,, K., Lo,, M. C., Huang,, Y. J., … Zhang,, D. E. (2014). Runx1 exon 6‐related alternative splicing isoforms differentially regulate hematopoiesis in mice. Blood, 123(24), 3760–3769. https://doi.org/10.1182/blood-2013-08-521252
Kronke,, J., Fink,, E. C., Hollenbach,, P. W., MacBeth,, K. J., Hurst,, S. N., Udeshi,, N. D., … Ebert,, B. L. (2015). Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature, 523(7559), 183–188. https://doi.org/10.1038/nature14610
Lam,, K., & Zhang,, D. E. (2012). RUNX1 and RUNX1‐ETO: Roles in hematopoiesis and leukemogenesis. Frontiers in Bioscience (Landmark Ed), 17, 1120–1139.
Lane,, S. W., Sykes,, S. M., Al‐Shahrour,, F., Shterental,, S., Paktinat,, M., Lo Celso,, C., … Gilliland,, D. G. (2010). The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood, 115(17), 3489–3497. https://doi.org/10.1182/blood-2009-11-251728
Lee,, G., Zheng,, Y., Cho,, S., Jang,, C., England,, C., Dempsey,, J. M., … Blenis,, J. (2017). Post‐transcriptional regulation of de novo lipogenesis by mTORC1‐S6K1‐SRPK2 signaling. Cell, 171(7), 1545–1558 e1518. https://doi.org/10.1016/j.cell.2017.10.037
Lee,, S. C., Dvinge,, H., Kim,, E., Cho,, H., Micol,, J. B., Chung,, Y. R., … Abdel‐Wahab,, O. (2016). Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nature Medicine, 22(6), 672–678. https://doi.org/10.1038/nm.4097
Lin,, S., & Fu,, X. D. (2007). SR proteins and related factors in alternative splicing. Advances in Experimental Medicine and Biology, 623, 107–122.
Lindsley,, R. C., Mar,, B. G., Mazzola,, E., Grauman,, P. V., Shareef,, S., Allen,, S. L., … Ebert,, B. L. (2015). Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood, 125(9), 1367–1376. https://doi.org/10.1182/blood-2014-11-610543
Liu,, K. J., Arron,, J. R., Stankunas,, K., Crabtree,, G. R., & Longaker,, M. T. (2007). Chemical rescue of cleft palate and midline defects in conditional GSK‐3beta mice. Nature, 446(7131), 79–82. https://doi.org/10.1038/nature05557
Lower,, K. M., Turner,, G., Kerr,, B. A., Mathews,, K. D., Shaw,, M. A., Gedeon,, A. K., … Gecz,, J. (2002). Mutations in PHF6 are associated with Borjeson–Forssman–Lehmann syndrome. Nature Genetics, 32(4), 661–665. https://doi.org/10.1038/ng1040
Lynch,, K. W. (2007). Regulation of alternative splicing by signal transduction pathways. Advances in Experimental Medicine and Biology, 623, 161–174.
Lynch,, K. W., & Weiss,, A. (2000). A model system for activation‐induced alternative splicing of CD45 pre‐mRNA in T cells implicates protein kinase C and Ras. Molecular and Cellular Biology, 20(1), 70–80.
Martelli,, A. M., Evangelisti,, C., Chappell,, W., Abrams,, S. L., Basecke,, J., Stivala,, F., … McCubrey,, J. A. (2011). Targeting the translational apparatus to improve leukemia therapy: Roles of the PI3K/PTEN/Akt/mTOR pathway. Leukemia, 25(7), 1064–1079. https://doi.org/10.1038/leu.2011.46
Martinez,, N. M., Agosto,, L., Qiu,, J., Mallory,, M. J., Gazzara,, M. R., Barash,, Y., … Lynch,, K. W. (2015). Widespread JNK‐dependent alternative splicing induces a positive feedback loop through CELF2‐mediated regulation of MKK7 during T‐cell activation. Genes %26 Development, 29(19), 2054–2066. https://doi.org/10.1101/gad.267245.115
Martinez,, N. M., & Lynch,, K. W. (2013). Control of alternative splicing in immune responses: Many regulators, many predictions, much still to learn. Immunological Reviews, 253(1), 216–236. https://doi.org/10.1111/imr.12047
Martinez,, N. M., Pan,, Q., Cole,, B. S., Yarosh,, C. A., Babcock,, G. A., Heyd,, F., … Lynch,, K. W. (2012). Alternative splicing networks regulated by signaling in human T cells. RNA, 18(5), 1029–1040. https://doi.org/10.1261/rna.032243.112
McCubrey,, J. A., Steelman,, L. S., Bertrand,, F. E., Davis,, N. M., Abrams,, S. L., Montalto,, G., … Martelli,, A. M. (2014). Multifaceted roles of GSK‐3 and Wnt/beta‐catenin in hematopoiesis and leukemogenesis: Opportunities for therapeutic intervention. Leukemia, 28(1), 15–33. https://doi.org/10.1038/leu.2013.184
McManus,, E. J., Sakamoto,, K., Armit,, L. J., Ronaldson,, L., Shpiro,, N., Marquez,, R., & Alessi,, D. R. (2005). Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO Journal, 24(8), 1571–1583.
Meacham,, C. E., Lawton,, L. N., Soto‐Feliciano,, Y. M., Pritchard,, J. R., Joughin,, B. A., Ehrenberger,, T., … Hemann,, M. T. (2015). A genome‐scale in vivo loss‐of‐function screen identifies Phf6 as a lineage‐specific regulator of leukemia cell growth. Genes %26 Development, 29(5), 483–488. https://doi.org/10.1101/gad.254151.114
Meggendorfer,, M., Roller,, A., Haferlach,, T., Eder,, C., Dicker,, F., Grossmann,, V., … Schnittger,, S. (2012). SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood, 120(15), 3080–3088. https://doi.org/10.1182/blood-2012-01-404863
Mian,, S. A., Rouault‐Pierre,, K., Smith,, A. E., Seidl,, T., Pizzitola,, I., Kizilors,, A., … Mufti,, G. J. (2015). SF3B1 mutant MDS‐initiating cells may arise from the haematopoietic stem cell compartment. Nature Communications, 6, 10004. https://doi.org/10.1038/ncomms10004
Michelle,, L., Cloutier,, A., Toutant,, J., Shkreta,, L., Thibault,, P., Durand,, M., … Chabot,, B. (2012). Proteins associated with the exon junction complex also control the alternative splicing of apoptotic regulators. Molecular and Cellular Biology, 32(5), 954–967. https://doi.org/10.1128/MCB.06130-11
Mikesch,, J. H., Steffen,, B., Berdel,, W. E., Serve,, H., & Muller‐Tidow,, C. (2007). The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia, 21(8), 1638–1647. https://doi.org/10.1038/sj.leu.2404732
Misteli,, T., Caceres,, J. F., Clement,, J. Q., Krainer,, A. R., Wilkinson,, M. F., & Spector,, D. L. (1998). Serine phosphorylation of SR proteins is required for their recruitment to sites of transcription in vivo. Journal of Cell Biology, 143(2), 297–307.
Morgan,, R. G., Pearn,, L., Liddiard,, K., Pumford,, S. L., Burnett,, A. K., Tonks,, A., & Darley,, R. L. (2013). Gamma‐catenin is overexpressed in acute myeloid leukemia and promotes the stabilization and nuclear localization of beta‐catenin. Leukemia, 27(2), 336–343. https://doi.org/10.1038/leu.2012.221
Muraki,, M., Ohkawara,, B., Hosoya,, T., Onogi,, H., Koizumi,, J., Koizumi,, T., … Hagiwara,, M. (2004). Manipulation of alternative splicing by a newly developed inhibitor of Clks. Journal of Biological Chemistry, 279(23), 24246–24254. https://doi.org/10.1074/jbc.M314298200
Murano,, K., Okuwaki,, M., Hisaoka,, M., & Nagata,, K. (2008). Transcription regulation of the rRNA gene by a multifunctional nucleolar protein, B23/nucleophosmin, through its histone chaperone activity. Molecular and Cellular Biology, 28(10), 3114–3126. https://doi.org/10.1128/MCB.02078-07
Myers,, R. L., Yousefi,, M., Lengner,, C. J., & Klein,, P. S. (2018). Wnt signaling in intestinal stem cells and cancer. In P. Boffetta & P. Hainaut (Eds.), Encyclopedia of Cancer, Cambridge, MA: Academic Press.
Nonaka,, S., Hough,, C. J., & Chuang,, D. M. (1998). Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N‐methyl‐D‐aspartate receptor‐mediated calcium influx. Proceedings of the National Academy of Sciences of the United States of America, 95(5), 2642–2647.
Okuwaki,, M., Tsujimoto,, M., & Nagata,, K. (2002). The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23, is modulated by phosphorylation with a cell cycle‐dependent kinase and by association with its subtype. Molecular Biology of the Cell, 13(6), 2016–2030. https://doi.org/10.1091/mbc.02-03-0036
Pan,, Q., Shai,, O., Lee,, L. J., Frey,, B. J., & Blencowe,, B. J. (2008). Deep surveying of alternative splicing complexity in the human transcriptome by high‐throughput sequencing. Nature Genetics, 40(12), 1413–1415. https://doi.org/10.1038/ng.259
Pap,, M., & Cooper,, G. M. (1998). Role of glycogen synthase kinase‐3 in the phosphatidylinositol 3‐kinase/Akt cell survival pathway. Journal of Biological Chemistry, 273(32), 19929–19932.
Papaemmanuil,, E., Cazzola,, M., Boultwood,, J., Malcovati,, L., Vyas,, P., Bowen,, D., … Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. (2011). Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. New England Journal of Medicine, 365(15), 1384–1395. https://doi.org/10.1056/NEJMoa1103283
Piao,, S., Lee,, S. H., Kim,, H., Yum,, S., Stamos,, J. L., Xu,, Y., … Ha,, N. C. (2008). Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta‐catenin signaling. PLoS One, 3(12), e4046. https://doi.org/10.1371/journal.pone.0004046
Picton,, C., Woodgett,, J., Hemmings,, B., & Cohen,, P. (1982). Multisite phosphorylation of glycogen synthase from rabbit skeletal muscle. Phosphorylation of site 5 by glycogen synthase kinase‐5 (casein kinase‐II) is a prerequisite for phosphorylation of sites 3 by glycogen synthase kinase‐3. FEBS Letters, 150(1), 191–196.
Pimentel,, H., Parra,, M., Gee,, S. L., Mohandas,, N., Pachter,, L., & Conboy,, J. G. (2016). A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis. Nucleic Acids Research, 44(2), 838–851. https://doi.org/10.1093/nar/gkv1168
Polakis,, P. (2000). Wnt signaling and cancer. Genes %26 Development, 14(15), 1837–1851.
Poorkaj,, P., Bird,, T. D., Wijsman,, E., Nemens,, E., Garruto,, R. M., Anderson,, L., … Schellenberg,, G. D. (1998). Tau is a candidate gene for chromosome 17 frontotemporal dementia. Annals of Neurology, 43(6), 815–825.
Prasad,, J., Colwill,, K., Pawson,, T., & Manley,, J. L. (1999). The protein kinase Clk/Sty directly modulates SR protein activity: Both hyper‐ and hypophosphorylation inhibit splicing. Molecular and Cellular Biology, 19(10), 6991–7000.
Qiu,, J., Zhou,, B., Thol,, F., Zhou,, Y., Chen,, L., Shao,, C., … Heuser,, M. (2016). Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators. RNA, 22(10), 1535–1549. https://doi.org/10.1261/rna.056101.116
Ran,, D., Shia,, W. J., Lo,, M. C., Fan,, J. B., Knorr,, D. A., Ferrell,, P. I., … Zhang,, D. E. (2013). RUNX1a enhances hematopoietic lineage commitment from human embryonic stem cells and inducible pluripotent stem cells. Blood, 121(15), 2882–2890. https://doi.org/10.1182/blood-2012-08-451641
Saliba,, J., Saint‐Martin,, C., Di Stefano,, A., Lenglet,, G., Marty,, C., Keren,, B., … Plo,, I. (2015). Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nature Genetics, 47(10), 1131–1140. https://doi.org/10.1038/ng.3380
Schneider,, R. K., Adema,, V., Heckl,, D., Jaras,, M., Mallo,, M., Lord,, A. M., … Ebert,, B. L. (2014). Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell, 26(4), 509–520. https://doi.org/10.1016/j.ccr.2014.08.001
Shandilya,, J., Senapati,, P., Dhanasekaran,, K., Bangalore,, S. S., Kumar,, M., Kishore,, A. H., … Kundu,, T. K. (2014). Phosphorylation of multifunctional nucleolar protein nucleophosmin (NPM1) by aurora kinase B is critical for mitotic progression. FEBS Letters, 588(14), 2198–2205. https://doi.org/10.1016/j.febslet.2014.05.014
Shav‐Tal,, Y., & Zipori,, D. (2002). PSF and p54(nrb)/NonO—multi‐functional nuclear proteins. FEBS Letters, 531(2), 109–114.
Shepard,, P. J., & Hertel,, K. J. (2009). The SR protein family. Genome Biology, 10(10), 242. https://doi.org/10.1186/gb-2009-10-10-242
Shin,, C., Feng,, Y., & Manley,, J. L. (2004). Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature, 427(6974), 553–558. https://doi.org/10.1038/nature02288
Shin,, C., & Manley,, J. L. (2004). Cell signalling and the control of pre‐mRNA splicing. Nature Reviews. Molecular Cell Biology, 5(9), 727–738. https://doi.org/10.1038/nrm1467
Shinde,, M. Y., Sidoli,, S., Kulej,, K., Mallory,, M. J., Radens,, C. M., Reicherter,, A. L., … Klein,, P. S. (2017). Phosphoproteomics reveals that glycogen synthase kinase‐3 phosphorylates multiple splicing factors and is associated with alternative splicing. Journal of Biological Chemistry, 292(44), 18240–18255. https://doi.org/10.1074/jbc.M117.813527
Shirai,, C. L., Tripathi,, M., Ley,, J. N., Ndonwi,, M., White,, B. S., Tapia,, R., … Walter,, M. J. (2015). Preclinical activity of splicing modulators in U2AF1 mutant MDS/AML. Blood, 126(23), 1653.
Shultz,, J. C., Goehe,, R. W., Wijesinghe,, D. S., Murudkar,, C., Hawkins,, A. J., Shay,, J. W., … Chalfant,, C. E. (2010). Alternative splicing of caspase 9 is modulated by the phosphoinositide 3‐kinase/Akt pathway via phosphorylation of SRp30a. Cancer Research, 70(22), 9185–9196. https://doi.org/10.1158/0008-5472.CAN-10-1545
Simon,, M., Grandage,, V. L., Linch,, D. C., & Khwaja,, A. (2005). Constitutive activation of the Wnt/beta‐catenin signalling pathway in acute myeloid leukaemia. Oncogene, 24(14), 2410–2420. https://doi.org/10.1038/sj.onc.1208431
Soda,, M., Willert,, K., Kaushansky,, K., Geddis,, A. E., & Ibarra,, Y. M. (2008). Inhibition of GSK‐3beta promotes survival and proliferation of megakaryocytic cells through a beta‐catenin‐independent pathway. Cellular Signalling, 20(12), 2317–2323.
Somervaille,, T. C., Linch,, D. C., & Khwaja,, A. (2001). Growth factor withdrawal from primary human erythroid progenitors induces apoptosis through a pathway involving glycogen synthase kinase‐3 and Bax. Blood, 98(5), 1374–1381.
Soto‐Feliciano,, Y. M., Bartlebaugh,, J. M. E., Liu,, Y., Sanchez‐Rivera,, F. J., Bhutkar,, A., Weintraub,, A. S., … Hemann,, M. T. (2017). PHF6 regulates phenotypic plasticity through chromatin organization within lineage‐specific genes. Genes %26 Development, 31(10), 973–989. https://doi.org/10.1101/gad.295857.117
Spillantini,, M. G., Murrell,, J. R., Goedert,, M., Farlow,, M. R., Klug,, A., & Ghetti,, B. (1998). Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proceedings of the National Academy of Sciences of the United States of America, 95(13), 7737–7741.
Staal,, F. J., & Clevers,, H. C. (2005). WNT signalling and haematopoiesis: A WNT–WNT situation. Nature Reviews. Immunology, 5(1), 21–30.
Stamm,, S. (2008). Regulation of alternative splicing by reversible protein phosphorylation. Journal of Biological Chemistry, 283(3), 1223–1227. https://doi.org/10.1074/jbc.R700034200
Sutherland,, C. (2011). What are the bona fide GSK3 substrates? International Journal of Alzheimer`s Disease, 2011, 505607–505623. https://doi.org/10.4061/2011/505607
Tanaka,, T., Tanaka,, K., Ogawa,, S., Kurokawa,, M., Mitani,, K., Nishida,, J., … Hirai,, H. (1995). An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms. EMBO Journal, 14(2), 341–350.
Tarapore,, P., Shinmura,, K., Suzuki,, H., Tokuyama,, Y., Kim,, S. H., Mayeda,, A., & Fukasawa,, K. (2006). Thr199 phosphorylation targets nucleophosmin to nuclear speckles and represses pre‐mRNA processing. FEBS Letters, 580(2), 399–409. https://doi.org/10.1016/j.febslet.2005.12.022
Tickenbrock,, L., Schwable,, J., Wiedehage,, M., Steffen,, B., Sargin,, B., Choudhary,, C., … Serve,, H. (2005). Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood, 105(9), 3699–3706. https://doi.org/10.1182/blood-2004-07-2924
Todd,, M. A., Ivanochko,, D., & Picketts,, D. J. (2015). PHF6 degrees of separation: The multifaceted roles of a chromatin adaptor protein. Genes (Basel), 6(2), 325–352. https://doi.org/10.3390/genes6020325
Todd,, M. A., & Picketts,, D. J. (2012). PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex. Journal of Proteome Research, 11(8), 4326–4337. https://doi.org/10.1021/pr3004369
Tran,, H., & Polakis,, P. (2012). Reversible modification of adenomatous polyposis coli (APC) with K63‐linked polyubiquitin regulates the assembly and activity of the beta‐catenin destruction complex. Journal of Biological Chemistry, 287(34), 28552–28563. https://doi.org/10.1074/jbc.M112.387878
Valvezan,, A. J., & Klein,, P. S. (2011). GSK‐3 and Wnt signaling in neurogenesis and bipolar disorder. Frontiers in Molecular Neuroscience, 5, 1. https://doi.org/10.3389/fnmol.2012.00001
Valvezan,, A. J., Zhang,, F., Diehl,, J. A., & Klein,, P. S. (2012). Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase‐3 (GSK‐3) activity. Journal of Biological Chemistry, 287(6), 3823–3832. https://doi.org/10.1074/jbc.M111.323337
Van Vlierberghe,, P., Palomero,, T., Khiabanian,, H., Van der Meulen,, J., Castillo,, M., Van Roy,, N., … Ferrando,, A. (2010). PHF6 mutations in T‐cell acute lymphoblastic leukemia. Nature Genetics, 42(4), 338–342. https://doi.org/10.1038/ng.542
Van Vlierberghe,, P., Patel,, J., Abdel‐Wahab,, O., Lobry,, C., Hedvat,, C. V., Balbin,, M., … Ferrando,, A. (2011). PHF6 mutations in adult acute myeloid leukemia. Leukemia, 25(1), 130–134. https://doi.org/10.1038/leu.2010.247
Vaquero‐Garcia,, J., Barrera,, A., Gazzara,, M. R., Gonzalez‐Vallinas,, J., Lahens,, N. F., Hogenesch,, J. B., … Barash,, Y. (2016). A new view of transcriptome complexity and regulation through the lens of local splicing variations. eLife, 5, e11752. https://doi.org/10.7554/eLife.11752
Wahl,, M. C., Will,, C. L., & Luhrmann,, R. (2009). The spliceosome: Design principles of a dynamic RNP machine. Cell, 136(4), 701–718. https://doi.org/10.1016/j.cell.2009.02.009
Wang,, C., Chua,, K., Seghezzi,, W., Lees,, E., Gozani,, O., & Reed,, R. (1998). Phosphorylation of spliceosomal protein SAP 155 coupled with splicing catalysis. Genes %26 Development, 12(10), 1409–1414.
Wang,, E. T., Sandberg,, R., Luo,, S., Khrebtukova,, I., Zhang,, L., Mayr,, C., … Burge,, C. B. (2008). Alternative isoform regulation in human tissue transcriptomes. Nature, 456(7221), 470–476. https://doi.org/10.1038/nature07509
Wang,, J., Fernald,, A. A., Anastasi,, J., Le Beau,, M. M., & Qian,, Z. (2010). Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood, 115(17), 3481–3488. https://doi.org/10.1182/blood-2009-11-251835
Wang,, J., Leung,, J. W., Gong,, Z., Feng,, L., Shi,, X., & Chen,, J. (2013). PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis. Journal of Biological Chemistry, 288(5), 3174–3183. https://doi.org/10.1074/jbc.M112.414839
Wang,, S., Venkatraman,, V., Crowgey,, E. L., Liu,, T., Fu,, Z., Holewinski,, R. J., … Van Eyk,, J. E. (2018). Protein S‐nitrosylation controls glycogen synthase kinase 3beta function independent of its phosphorylation state. Circulation Research, 122, 1517–1531. https://doi.org/10.1161/CIRCRESAHA.118.312789
Wang,, Y., Krivtsov,, A. V., Sinha,, A. U., North,, T. E., Goessling,, W., Feng,, Z., … Armstrong,, S. A. (2010). The Wnt/beta‐catenin pathway is required for the development of leukemia stem cells in AML. Science, 327(5973), 1650–1653. https://doi.org/10.1126/science.1186624
White,, E. S., Sagana,, R. L., Booth,, A. J., Yan,, M., Cornett,, A. M., Bloomheart,, C. A., … Muro,, A. F. (2010). Control of fibroblast fibronectin expression and alternative splicing via the PI3K/Akt/mTOR pathway. Experimental Cell Research, 316(16), 2644–2653. https://doi.org/10.1016/j.yexcr.2010.06.028
Wilson,, G. M., Lu,, J., Sutphen,, K., Suarez,, Y., Sinha,, S., Brewer,, B., … Brewer,, G. (2003). Phosphorylation of p40AUF1 regulates binding to A + U‐rich mRNA‐destabilizing elements and protein‐induced changes in ribonucleoprotein structure. Journal of Biological Chemistry, 278(35), 33039–33048. https://doi.org/10.1074/jbc.M305775200
Wong,, A. C. H., Rasko,, J. E. J., & Wong,, J. J. (2018). We skip to work: Alternative splicing in normal and malignant myelopoiesis. Leukemia, 32(5), 1081–1093. https://doi.org/10.1038/s41375-018-0021-4
Wong,, J. J., Ritchie,, W., Ebner,, O. A., Selbach,, M., Wong,, J. W., Huang,, Y., … Rasko,, J. E. (2013). Orchestrated intron retention regulates normal granulocyte differentiation. Cell, 154(3), 583–595. https://doi.org/10.1016/j.cell.2013.06.052
Xiao,, S. H., & Manley,, J. L. (1997). Phosphorylation of the ASF/SF2 RS domain affects both protein‐protein and protein‐RNA interactions and is necessary for splicing. Genes %26 Development, 11(3), 334–344.
Xiao,, S. H., & Manley,, J. L. (1998). Phosphorylation‐dephosphorylation differentially affects activities of splicing factor ASF/SF2. EMBO Journal, 17(21), 6359–6367. https://doi.org/10.1093/emboj/17.21.6359
Xu,, C., Kim,, N. G., & Gumbiner,, B. M. (2009). Regulation of protein stability by GSK3 mediated phosphorylation. Cell Cycle, 8(24), 4032–4039. https://doi.org/10.4161/cc.8.24.10111
Xu,, Q., Simpson,, S. E., Scialla,, T. J., Bagg,, A., & Carroll,, M. (2003). Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood, 102(3), 972–980. https://doi.org/10.1182/blood-2002-11-3429
Yeung,, J., Esposito,, M. T., Gandillet,, A., Zeisig,, B. B., Griessinger,, E., Bonnet,, D., & So,, C. W. (2010). Beta‐catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell, 18(6), 606–618. https://doi.org/10.1016/j.ccr.2010.10.032
Yilmaz,, O. H., Valdez,, R., Theisen,, B. K., Guo,, W., Ferguson,, D. O., Wu,, H., & Morrison,, S. J. (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemia‐initiating cells. Nature, 441(7092), 475–482.
Yin,, L., Wang,, J., Klein,, P. S., & Lazar,, M. A. (2006). Nuclear receptor Rev‐erbalpha is a critical lithium‐sensitive component of the circadian clock. Science, 311(5763), 1002–1005.
Yoshida,, K., Sanada,, M., Shiraishi,, Y., Nowak,, D., Nagata,, Y., Yamamoto,, R., … Ogawa,, S. (2011). Frequent pathway mutations of splicing machinery in myelodysplasia. Nature, 478(7367), 64–69. https://doi.org/10.1038/nature10496
Ysebaert,, L., Chicanne,, G., Demur,, C., De Toni,, F., Prade‐Houdellier,, N., Ruidavets,, J. B., … Racaud‐Sultan,, C. (2006). Expression of beta‐catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia, 20(7), 1211–1216. https://doi.org/10.1038/sj.leu.2404239
Zhang,, J., Grindley,, J. C., Yin,, T., Jayasinghe,, S., He,, X. C., Ross,, J. T., … Li,, L. (2006). PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature, 441(7092), 518–522.
Zhang,, W., DePaoli‐Roach,, A. A., & Roach,, P. J. (1993). Mechanisms of multisite phosphorylation and inactivation of rabbit muscle glycogen synthase. Archives of Biochemistry and Biophysics, 304(1), 219–225.
Zhou,, Z., & Fu,, X. D. (2013). Regulation of splicing by SR proteins and SR protein‐specific kinases. Chromosoma, 122(3), 191–207. https://doi.org/10.1007/s00412-013-0407-z

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Glycogen synthase kinase‐3 and alternative splicing

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox