Regulation of RNA Polymerase 212

Supplementary Material Table 5- Drosophila protein kinases with cell cycle phenotypes and their putative orthologues.

Name /Link Putative Orthologues Previously Known Functionsa to FlyBase Link to InParanoid (Human, Drosophila, C.elegans; S.pombe, S.cerevisae) database Ack HS-Ack1 Nonreceptor tyrosine kinase – effector of cdc42 1; dorsal closure, expressed highly in mitotic domains2 aurA HS-Aurora A Regulates entry into mitosis; centrosome maturation and spindle formation; mutants display defects in centrosome and spindle behaviour3 aurora B HS-AurB*; SC-Ipl1p* Chromosome alignment & spindle assembly checkpoint & cytokinesis; chromosome condensation & cytokinesis3 BubR1 HS-BubR1; SC-Bub1 Spindle assembly checkpoint4;spindle assembly checkpoint-similar role to S. cerevisiae mad3 ; contains KEN box5, mutants show lower MI and faster exit from mitosis6 cdc2 HS-CDK1; SC-cdc28; Regulates G2 to M-phase transition and entry to mitosis7; activation of the APC8; G2/M transition SP-cdc2 of mitotic cycle9 cdc2c HS CDK2 G1/S transition and S phase progression; G1/S transition and S phase Cdk4 HS-CDK6/4 G1/S transition; Cell growth10,11 Cdk8 HS-CDK8 Regulation of RNA polymerase 212 Cdk9 HS-CDK9 Interacts with pRb13. Regulation of RNA polymerase 214 CG10522 HS-CIT Cytokinesis15; cytokinesis16 CG10967 HS-ULK2; CE-Unc- Axon morphogenesis and elongation, may signal through ras17 51 CG1344 HS-Pace-1;CS- Cell spreading and motility - colocalises with ezrin in lamellipodia18 SCY1* CG14030/ HS-BUB1*; SC-Bub1 Spindle assembly checkpoint; Does not contain KEN box; functionally similar to HS Bub1 and SC BUB1 Bub15 CG15072 HS-KIAA0999/QSK AMPk-related kinase activated by LKB19 CG1951 HS- NTKL localises to the centrosomes during mitosis20 KIAA1360;NTKL*;SC -SCY1 CG2309 HS-ERK8 Activated by SRC21 CG2829 HS-TLK1 /2 Chromatin assembly following DNA replication; DNA damage checkpoint target22; essential for nuclear divisions, cell viability and chromatin assembly23. CG3216 HS-Atrial natriuretic G-protein coupled receptor protein signaling pathway- respond to cGMP24 ; may inhibit peptide receptor * proliferation25

CG32742 HS-cdc7; SC-cdc7 Cdc7-related kinase - DNA replication26 CG5483 HS-KIAA1790 Similarity to leucine-rich repeat kinase (LRRK1) CG6498 HS-MAST1 or 2 MAST2 localizes to spermatid manchette through other MAPS; activates NFKB (Mus musculus)27,28 CG7094 HS-CSNK1A1*; CE- Wnt signalling29 kin-19* CG7156 HS-RSK-LIKE Novel RSKL similar to JIL, S6K and S6KII PROTEIN CG7236 HS-CDKL1 Cdc2-related kinase 1; involved in gliosis30 CG7597 HS-CRK7/CDC2L5; Cdc2-related protein kinase 7; MPM-2 antigen-possibly involved in splicing and transcription31; CE-B0285.1 RNAi mutants show slow developmental growth32 CG7643 HS-TTK; SC-MPS1 Spindle assembly checkpoint33 and centrosome duplication34; duplication of spindle pole bodies & spindle assembly checkpoint4 CG8565 HS-SRPK2*; CE- Pre-mRNA splicing machinery; phosphorylate SR proteins; SPK-1, required for embryogenesis and SPK-1* germline development35 CG9488 HS-DDR2* Extracellular matrix remodelling36,37 CkIalpha HS-CSNK1A1 Interacts with Axin to inhibit JNK cascade; promotes armadilllo degradation38; induced after DNA damage39 CkIIalpha HS-CK2A1;SC-CKA1 Associated with APC - phosphorylates p53; multiple signalling pathways40; circadian clock dnt HS-RYK Up-regulated in ovarian cancer41; Interacts genetically with drl Doa HS- CLK2/3/4; SP- Lammer dual specificity kinase 2; meiotic progression42; septation and proliferation43 Lkh1 drl HS-RYK Receptor tyrosine kinase; axon pathfinding; Wnt receptor signalling pathway Eip63E HS-PFTAIRE-1 PFTAIRE (cdc2-related) protein kinase 1; Ecdysone-induced protein 63E required for embryonic and larval development for HS-PRKG1 NO/cGMP/cGK signaling - negative regulator of cell proliferation44;response to hypoxia; behaviour fray HS-OSR1 or SPAK Oxidative stress response- phosphorylates PAK1; MAP4K in JNK pathway45; Nerve ensheathment fs(1)h HS-BRD4/MCAP or BRD4 associates with chromosomes and injection of antibodies arrests cells in G2/M46; RING3 is RING3* linked to human leukaemia; trans-activates genes dependent on E2F47 Gcn2 HS-GCN2; SC-GCN2 Phosphorylates eIF2alpha in amino acid deprivation, signalling the activation of NFKB 48; protein synthesis in stress response gek HSCDC42BP;CE- Abnormal accumulation of F actin in oogenesis; RNAi gives dumpy & slow growing embryos K08B12.5. gish HS-CK1G3;CE- Glial cell migration; Mitotic spindle orientation49; growth and division - cell morphogenesis and Y106G6E.6;SC- cytokinesis50. YCK1 or 2 grp HS-Chk1 Replication and DNA damage G2 checkpoint51; cell cycle coordination in syncytial embryo; mutants show rapid entry into M, defects in chromosome condensation and degradation of cyclin A

1 gwl HS-FLJ14813; SC- Candidate gene for autosomal dominant thrombocytopenia on human chromosome 1052; rim15; SP-cek1 * sporulation and meiosis53; cek1 is a suppressor of cut 8 (necessary for anaphase)54; mutants show chromosome condensation defects55 hippo HS-STK4 or 3; SC- Induction of apoptosis56; apoptosis- mutants have higher levels of cyclinE and DIAP1;mitotic exit cdc15* network57 hop HS-JAK2/3/1 JAK-STAT signalling; haemocyte proliferation & cell fate determination- interacts with CDK458 htl HS-FGR2/3 /1/4 Receptor tyrosine kinase for FGFs; interacts with ras; important for cell migration in several mesodermal lineages; pbl may act downstream of htl in regulating cell shape59 ik2 HS- NAK/TBK1 NFK beta signalling; NFK beta signalling - defense response. Ilk HS-ILK1 or ILK2; CE- Phosphorylates GSK-3 - connects integrins to actin cytoskeleton; upregulated in several ILK cancers60; focal adhesions of cytoskeleton inaC SC-PKC1 Mutants have behaviour defects; morphogenesis checkpoint61 InR HS-IGF1R Insulin-like growth factor I receptor-mediates cell proliferation; signals to MAPK/ras and to PI3K 62; mutants are long lived and have a smaller body JIL-1 HS-RPS6KA5/4 Activated by MAPK and SAPK/p38; phosphorylates CREB63; phosphorylation of Histone H364 ; activation of NF-kappaB65; histone H3 phosphorylation; transcriptional control, maintenance of chromatin structure66 lic HS- MAP2K3 /6 Stress response-phosphorylates MAPK p3867; asymmetric development of the egg . lkb1 HS-lkb1 Tumour suppressor - activates 13 kinases of the AMPK subfamily19; oocyte microtubule organization. MAPk-Ak2 HS-MAPKAPK2/3 Activated in response to IFN in the p38 pathway68 mbt HS-PAK7/5/4 Interacts with Cdc42 and Rac - promotes filopodium formation and cell migration69,70;cytoskeleton & photoreceptor development Mkk4 HS-MAP2K4 JAK-STAT and JNK cascades -links response to stress to cell cycle progression71 mnb HS-DyrK1;CE-mbk1 Candidate target of Down’s Syndrome; mutants have small brains; spindle positioning and or 2 * asymmetric cell division72 Myt1 HS-Myt1 Negative regulator of CDK1; regulates mitotic entry nmo HS-NemoLK; CE- Wnt signalling - polarization/rotation of cells - NFKB interactor; embryogenesis W06F12.1 Nrk HS-MUSK Muscle specific tyrosine kinase receptor; interacts with ras in oocytes par-1 HS-MARK3 Phosphorylates CDC25C regulating interaction with 14-3-373; regulator of oocyte cytoskeleton; interacts genetically with lkb1; regulator of wnt signalling PhK HS-PHKG Metabolism74; embryonic morphogenesis Pk61C HS-PDK1 Activation of p70s6k75; upstream effector of S6k76;Mutant cells are smaller. Pk92B HS-ASK1/MEKK5/1; Apoptosis77; stress & morphogenesis checkpoint 61 SC-Bck1 * Pka-C2 HM-PKA-Cbeta*; SC- Regulates mitotic progression through cdc2078 PKA1 or 2* pll HS-IRAK1 Mediates activation of NF-kappaB and MAPK pathways (JNK/p38)79; immunity polo HS-plk1; SC-cdc5 Multiple mitotic functions –cytokinesis80; multiple mitotic functions Pvr HS-VEGFR1/2/3 Vascular endothelial growth factor receptor 1 precursor; regulation of proliferation and cell migration81; organisation of actin cytoskeleton in cell migration82 Rok HS-ROCK Cytokinesis83; tissue polarity S6k HS-RPS6KB1 /2 Cell proliferation and growth84; interacts with Pk61C,Tor & Akt1 – Mutants cells are smaller85 S6kII HS-RSK3/2/1/46 Central nervous system development86; Phosphorylates tuberin inhibiting its ability to suppress mTor signalling87, Phosphorylation and inhibition of myt1 kinase 88-activates bub189 (Xenopus laevis) SAK HS-SAK Required for mitosis (Mus musculus)90 SNF1A HS-AMPK2;SC-SNF1 metabolic stress response; regulation of pol II and initiation of meiosis91 Src64B HS- FYN* regulation of actin polymerisation; contraction of actin/myosin during cellularization92; cell proliferation93 Taf1 HS-TafII250 TATA box binding protein associated – induces G1 progression through p5394; G2/M progression through transcriptional activation of string/cdc2595 tkv HS-BMPR1B Type I TGF receptor; cell growth and division - anterior/posterior patterning tor HS-RET* Mutants show disruption in anterior/posterior axis; Activates ras and STAT 96 Tor HS-FRAP1 Target of rapamycin – regulates G1/S transition97; Mutant cells are smaller and arrest in G198; growth control trbl HS-trb2/1/SKIP3 SKIP3 is upregulated in human tumours99; Negative regulator of CDK1; Induces Proteolysis of string and twine100 wee HS-Wee1; SP-wee 1* Mitotic checkpoint phosphorylation of CDK1; Wee1p phosphorylates Cdc2p on Tyr15101; regulates mitotic entry wts HS-LATS1 /2 Tumour suppressor; inhibits G2/M and promotes apoptosis102; mutants show overgrowth and abnormal morphogenesis; interacts genetically with CycA and cdc2 H. Sapiens (HS); C. elegans (CE); S. Cerevisiae (SC); S. Pombe (SP). We obtained orthologues from other organisms in the Inparanoid database103 (confidence value=0.05 or higher). We indicate the closest homologue after a BLAST104 search in NCBI, when the orthology is not clear (entries with *). a-Information on Drosophila phenotypes was taken from literature search and FlyBase (www.flybase.org). Information was also drawn from

2 WormBase(http://www.wormbase.org/), from the Budding Yeast Database (SGD)

(http://www.yeastgenome.org/) and from OMIM (Online Mendelian Inheritance of Men@ NCBI). Entries are shown in alphabetic order and more detail is given than in Table 1. Due to limitations of space we regret that it is not possible to mention all published works relevant to this table.

3 References

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