Coral: Clear and Customizable Visualization of Human Kinome Data

bioRxiv preprint doi: https://doi.org/10.1101/330274; this version posted May 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

Coral: Clear and customizable visualization of human kinome data

Kathleen S. Metz,1,* Erika M. Deoudes,2,* Matthew E. Berginski,3,4 Ivan Jimenez-Ruiz,5 Bulent Arman Aksoy,6 Jeff Hammerbacher,6 Shawn M. Gomez,3,4 and Douglas H. Phanstiel 2,7,8 1Curriculum in Genetics & Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA 2Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599, USAv 3Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC 27514, USA 4Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA 5Curriculum in Bioinformatics & Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA 6Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA 7Department of Cell Biology & Physiology, University of North Carolina, Chapel Hill, NC 27599, USA 8Correspondence: [email protected] *These authors contributed equally

Protein kinases represent one of the largest gene families Multiple paradigms have been established for representing in eukaryotes and play roles in a wide range of cell signal- kinome attributes. In 2002, Manning et al. generated a kinome ing processes and human diseases, making them attrac- map based on sequence similarity between publicly available tive targets for drug development. The human kinome is and predicted protein kinase domains and categorized the extensively featured in high-throughput studies generat- 518 known human kinases into nine superfamilies (Manning et al., 2002). This dendrogram was then modified in reference ing genomic, proteomic, and kinase profiling data. Cur- to other trees and manually refined into an aesthetically rent tools for visualizing kinase data in the context of the pleasing image in which branches are colored by kinase human kinome superfamily are limited to encoding data group and kinase names are HTML links to websites with through the addition of nodes to a low-resolution image information specific to each kinase (www.cellsignal.com). of the kinome tree. We present Coral, a user-friendly Several groups have manually modified this image, encoding interactive web application for visualizing both quantita- qualitative or quantitative kinase information in either tive and qualitative data. Unlike previous tools, Coral can branch color (Fleuren et al., 2016; Phanstiel et al., 2011) or encode data in three features (node color, node size, and in the color and size of circular nodes placed at the end of branch color), allows three modes of kinome visualization each branch (Hu et al., 2017; Li et al., 2016; Wu et al., 2016). (the traditional kinome tree as well as radial and dynam- These figures are powerful tools for data interpretation and ic-force networks) and generates high-resolution scalable communication but are labor intensive to create and often infeasible for large or more complex experimental data sets. vector graphic files suitable for publication without the To address this issue, several programs have been developed need for refinement in graphic editing software. Due to to automate kinome visualization including Kinome Render its user-friendly, interactive, and highly customizable (Chartier et al., 2013), the NCGC Kinome Viewer (tripod.nih. design, Coral is broadly applicable to high-throughput gov), and KinMap (Eid et al., 2017), which have been widely studies of the human kinome. The source code and web adopted by the kinase research community. Because these application are available at github.com/dphansti/Coral. existing methods encode information solely by adding nodes html and phanstiel-lab.med.unc.edu/Coral respectively. to the existing image created by Cell Signaling Technology, they suffer from three limitations: (1) they offer no ability to recolor kinase branches either for aesthetic purposes or to INTRODUCTION encode information, (2) they only feature a single paradigm he human kinome consists of over 500 different protein for kinome representation, the semi-quantitative tree, and (3) T kinases, which regulate a broad range of cellular they produce low-resolution images that are not well suited processes via substrate phosphorylation. These proteins for publication. have been implicated in a variety of diseases including Here we describe Coral, an interactive web application pathological hypertrophy (Heineke and Molkentin, 2006; for kinome annotation which allows encoding of qualitative Vlahos et al., 2003), rheumatoid arthritis (Gaestel et al., and quantitative kinase attributes in branch color, node 2009; Patterson et al., 2014), and cancer (Fleuren et al., 2016; color, and node size. Coral offers multiple modes of kinome Ventura and Nebreda, 2006). As a result, protein kinases are visualization including the traditional kinome tree, as well as common candidates for drug targets and are increasingly interactive static and dynamic network layouts enabled by the focus of large-scale studies (Cohen, 2002; Cohen and the D3 javascript library. Importantly, the images produced Alessi, 2013; Duong-Ly and Peterson, 2013; Hu et al., 2017; Li by Coral are highly customizable and can be downloaded et al., 2016; Wu et al., 2016). High-throughput approaches to as high-resolution, publication quality vector images. Coral study kinase abundance and activity–including proteomics, was designed to be user friendly and includes example genomics, and kinase profiling screens–have created a need data, extensive documentation, and example outputs for all to visualize and interpret results in the greater context of the features. human kinome.

1 bioRxiv preprint doi: https://doi.org/10.1101/330274; this version posted May 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

FGFR2FGFR3 A TRKC EphB2 FGFR1 TRKB FGFR4 TRKA KDR FLT1 FmS/CSFR EphB1 ROR2 EphA5 MUSK ROR1 Kit Ret EphB3 DDR2 Mer EphA3 Axl DDR1 Tyro/Sky FLT4 PDGFRα EphA4 FLT3 IRR PDGFRβ EphA6 IGF1R HER2 Yes InSR Met EGFR EphB4 Ron MLK3 Branch Color Src Atypical Kinases Ros MLK1 ALK TIE2 Lyn EphA7 LTK TIE1 log2 RNA (ES / fibroblast) RYK HER4 HCK Fyn MLK4 ADCK1 EphA8 CCK4/PTK7 MLK2 -3 0 3 Tnk1 Tyk2 ADCK5 Ack JAK1 Lck Fgr JAK2 ABC1 ADCK3 HER3 ADCK4 EphA2 JAK3 BLK ADCK2 ZAP70 ANKRD3SgK288 DLK TKL PYK2Syk LZK TK EphA1 FAK Lmr1 Chak1 Lmr2 ALK4 Chak2 RAF1 ITK FRK ZAK TGFβR1 TEC EphB6 KSR BRAF AlphaK3 Srm RIPK2 KSR2 Alpha EEF2K Node Color TXK IRAK1 BTK Brk Lmr3 IRAK3 LIMK1 ALK7 AlphaK2 ARAF Etk/BMX EphA10 LIMK2 BMPR1B AlphaK1 TESK1 ILK BMPR1A log2 RNA (ES / fibroblast) CTK RIPK3 TESK2 TAK1 ALK1 CSK HH498 ALK2 Brd2 -3 0 3 Arg ACtR2 Brd3 Abl Fes IRAK2 ACtR2B RIPK1 Brd Brd4 Fer TGFβR2 JAK3~b MEKK2/MAP3K2 BrdT JAK2~b LRRK1 MISR2 MEKK3/MAP3K3 LRRK2 BMPR2 ASK/MAP3K5 Tyk2~b SuRTK106 IRAK4 MAP3K8 STE ANPα JAK1~b MAP3K7 PDHK3 ANPβ MOS KHS1 MST1 YSK1 PDHK PDHK1 MST2 PDHK4 HSER HPK1 KHS2 MST3 SgK496 WNK1 BCKDK Node Size GCK MEKK6/MAP3K6 MST4 DYRK2 PBK WNK3 DYRK3 CYGD MAP3K4 ATM NRBP2 WNK2 HGK/ZC1 ES — RNA RPKM DYRK1A DYRK4 NRBP1 ATR DYRK1B CYGF MEKK1/MAP3K1 OSR1 MINK/ZC3 STLK3 TNIK/ZC2 mTOR/FRAP 0 100 MLKL WNK4 NRK/ZC4 STLK5 PIKK DNAPK PERK/PEK STLK6 MYO3A SgK307 SLK SMG1 PKR MYO3B HIPK1 HIPK3 GCN2 SgK424 LOK TRRAP SCYL3 TAO1 HIPK2 SCYL1 COT TAO2 SCYL2 NIK TAO3 PRP4 PAK1 RIOK3 CLK4 HIPK4 HRI PAK3 PAK4 CLK1 CLIK1 PAK2 RIOK1 CLK2 IRE1 MAP2K5 PAK5 RIO IRE2 CLIK1L RIOK2 CLK3 TBCK PAK6 MAP2K7 RNAseL MEK1/MAP2K1 GCN2~b MEK2/MAP2K2 TIFα TIFγ MSSK1 TTK SgK071 TIF1 SRPK2 KIS MKK3/MAP2K3 TIFβ MYT1 SEK1/MAP2K4MKK6/MAP2K6 CMGC SRPK1 CK2α1 Wee1 SgK196 CK1δ MAK CK2α2 CDC7 Wee1B TTBK1 GSK3β ICK PRPK CK1ε Haspin GSK3α MOK TTBK2 CK1α CDKL3 CK1α2 PINK1 CDKL2 SgK269 SgK493 VRK3 CK1γ2 CDKL1 CDKL5 ERK7 SgK396 SgK223 CK1γ1 CDKL4 ERK4 Slob NLK ERK3 SgK110 CK1γ3 SgK069 PIK3R4 Bub1 ERK5 SBK CK1 IKKα BubR1 VRK1 ERK1 IKKβ CDK7 IKKε PLK4 VRK2 ERK2 P38γ TBK1 MPSK1 JNK1 PITSLRE TLK2 P38δ JNK3JNK2 CDK10 GAK PLK3 AAK1 ULK3 TLK1 P38β CDK8 CAMKK1 CDK11 PLK1 PLK2 P38α CDK4 CCRK BARK1/GRK2 BIKE CAMKK2 RHODK/GRK1 CDK6 ULK1 BARK2/GRK3 Fused GRK5 GRK7 PFTAIRE2 ULK2 ULK4 SgK494 PFTAIRE1 CDK9 Nek6 GRK6 GRK4 Nek7 RSKL1 PCTAIRE2 Nek8 Nek10 SgK495 PASK PDK1 MSK1 RSKL2 RSK1/p90RSK Nek9 Lkb1 MSK2 PCTAIRE1PCTAIRE3 CDK5CRK7CHED RSK4 RSK2 Nek2 CHK1 p70S6K RSK3 Akt2/PKBβ Nek11 AurA/Aur2 p70S6Kβ Akt1/PKBα CDC2/CDK1 Akt3/PKBγ CDK3 Nek4 SGK1 CDK2 AurB/Aur1 Trb3 Pim1 PKN1/PRK1 SGK2SGK3 Pim2 AurC/Aur3 LATS1 Nek3 PKG2 PKN2/PRK2 Trb2 Pim3 LATS2 PKG1 Nek5 NDR1 PKN3 Trb1 Obscn~b NDR2 PRKY YANK1 PRKX Nek1 SPEG~b MAST3 PKCη Obscn MASTL PKCζ PKCε STK33 YANK2 PKCι PKCδ SPEG YANK3 PKCθ PKAγ PKCγ TTN PKAα MAST2 PKAβ Trio smMLCK Trad ROCK1 PKCα TSSK4 CHK2 HUNK ROCK2 PKCβ skMLCK SNRK DMPK SSTK MAST4 MAST1 DRAK2 NIM1 CRIK TSSK3 PKD2 DRAK1 DCAMKL3 AGC SgK085 TSSK1 DCAMKL1 DMPK2 TSSK2 PKD1 DCAMKL2 caMLCK MELK PKD3 CASK DAPK3 DAPK2 VACAMKL MRCKβ PhKγ1 DAPK1 MAPKAPK5 PSKH1 MRCKα MNK1 PhKγ2 AMPKα2 PSKH2 MNK2 MAPKAPK2 AMPKα1 CaMK2γ CaMK2α CaMK2β BRSK2 MAPKAPK3CaMK2δ CaMK4 BRSK1 RSK4~b NuaK2 NuaK1 RSK1~b MSK1~b MSK2~b CaMK1β QSK RSK2~b RSK3~b CaMK1γ SIK QIK CAMK CaMK1α CaMK1δ MARK4 MARK1 MARK3 MARK2

CDKL1 CDKL3 CDKL2 CDKL4 CYGD CDKL5

HSER CYGF ANPα ANPβ

CK2α1 CK2α2 Node Color Fyn Fgr GSK3α CLK1 GSK3β CLK2 CLK3 CLK4 Lyn FRK BLK

EEF2K

Chak2 Chak1 AlphaK3 AlphaK2 AlphaK1 Brk MAK MOK TRRAP AGC ERK1 SMG1 HCK ERK2 ICK EphB1 mTOR/FRAP Yes DNAPK EphA1 ERK3 ATR EphA7 Src ATM Srm TIFγ TIFβ EGFR TIFα EphA10EphA8 Lck RIOK3 Atypical EphA5 RIOK2 EphB6 HER4 ALK2ALK1 RIOK1 EphA2 HER2 PDHK4 PDHK3 EphA3EphA6 PDHK1 EphB3 BMPR1A B BCKDK C CAMK EphA4 HER3 BMPR1BACtR2B BrdT Src Axl ALK7 Brd4 Mer BMPR2 Brd3 EphB4 Brd2 EphB2 TRKA ALK4TGFβR1TGFβR2 ADCK5 CK1 CSK TRKB DDR1 Tyro/Sky ACtR2 ADCK4 Eph FLT1 STKR1 ADCK3 TRKCDDR2 MISR2 ADCK2 CTK KDRFLT4 STKR2 ADCK1 CMGC EGFR FAK ZAP70 BTK Syk ITK Arg PYK2 Yes Etk/BMX Abl Ret Axl Srm Src Other Trk Lyn TXK DDR IGF1R DLKLZK Lck TEC Csk VEGFR IRR HCK Fes Fyn JNK1 Tec FAK MLK2 FRK RGC Abl InSR HH498 Fgr CCK4/PTK7 RYK Brk P38α FGFR2 Ret InsR Fer STKR MLK1 BLK P38β JNK2JNK3 ZAK MLK4 FGFR4 CCK4 Ryk Fer KSR LZK Tyro/Sky STE P38γ FGFR1 SuRTK106 Mer P38δ ERK1 FGFR Lmr1 MLK MLK3 Axl FGFR3 TK-UniqueTK Lmr Lmr3 HH498 Ack ZAK Tyk2~b TK TIE2 Tie Tnk1 Lmr2 JAK3~b p38 ERK2 JNK KSR JAK2~b TIE1 Sev Musk Ack BRAF ILK ILK JAK1~b ERK4 TAK1 Tyk2 TKL ERK7 PDGFR Syk ALK Jak RAF1 MLK TAK1 JAK3 ERK3 ERK1 FmS/CSFRPDGFRβ Met JAK2 KSR2ARAF JAK2 ERK5 Ror CDKL JAK1 MUSK Tyk2 RGC ERK3 PDGFRα ERK7 FLT3 Ros JakB LTK JAK3 RAF CK2 TXK ZAP70 CLK TEC LRRK2 GSK NLK ERK5 Kit JAK1 LRRK1 TESK2 ERK1 RCK ITK TESK1

eEF2K ChaK nmo Met ALK TRRAP Syk Ron ERK3 SMG1 BTK IRAK3 FRAP TESK DNAPK CHED ERK5 Etk/BMX MAPK ATR Tyk2~b ERK7 ATM Node Size CRK7 IRAK1 TIF1 ROR1 JAK1~b LRRK RIO3 TRKC IRAK2 RIO2 CDK10 ROR2 MLKL JNK RIO1 TRKB JAK2~bJAK3~b IRAK LISK LIMK LIMK2 nmo PDHK TRKA ES — RNA RPKM CDK3 IRAK4 CDK7 TKL-Unique LIMK1 BRD Tnk1 CDK2 PFTAIRE2 TKL Ack 0 100 CRK7 RSK3~b ABC1-D RIPK1 RSK1~b ABC1-A PFTAIRE1 RIPK ABC1-C TIE2 CDK2 CDK10 ANKRD3 RSK4~b ABC1-B TIE1 CDC2/CDK1 CDK7 RIPK2 RSK2~b Syk PCTAIRE2 PFTAIRE SgK288RIPK3 MSK1~b SuRTK106 CLK1CLK3 RSKb PCTAIRE3 CDC2 MAK MSK2~b RYK PCTAIRE CLK4 MOK Src PCTAIRE1 CCRKCDK CLK2 Ros CDK9 ICK MSKb CDK8CDK5 CLK RCK ADCK2 ROR2 CDK8 ADCK5 Axl CDK9 ROR1 CDK11 CDK5CDK4CDK11 CK2α1 CK2 SRPK2 ATM DNAPK ADCK1 JakB Ron CK2α2 CMGCSRPK ABC1-DABC1-C Met CDK6 MSSK1 mTOR/FRAP ADCK3 BRSK1BRSK2 CDK4 PITSLRE Jak Ret GSK SRPK1 ATR ATM ABC1-B RSKb MARK1 CDKL DNAPK ABC1-AADCK4 Pim1 SNRK PYK2 GSK3β ATRFRAP PDHK1PDHK4 MARK2 CDKL1CDKL4 ABC1 Pim3 PKD2PKD1 MELK MARK4 Tec FAK SMG1 BCKDKPDHK3 Pim2 GSK3α CDKL2 SMG1 PIKK PKD3 BRSK MARK3 PDGFRβ CDKL3CDKL5 PDHK MARK Trk PDGFRα TRRAP PSKH1 PhKγ2 Kit DYRK TRRAP TIFβ PSKH2 PhKγ1 DCAMKL2 SNRK PASK FmS/CSFR DYRK1ADYRK1 RIOK3 MELK RGC Ack Brd3 PIM DCAMKL1 FLT3 HIPK3 DYRK1B AtypicalTIF1TIFγ RIO3 Obscn PKD DCAMKL3 HUNKAMPKα1 Tie HIPK PRP4 Brd2 BRD PASK MUSK HIPK2 RIO Obscn~bTrad HUNKAMPK AMPKα2 MAPK Alpha TK-Unique ANPβ TIFα PSK PHK PIKK HIPK4 CYGD Brd4 RIO2 DCAMKL CAMKL Ryk LTK HIPK1 PRP4 BrdT RIOK2 SPEGSPEG~b CHK2 RIO DYRK2 CYGF ALK RGC RIO1 Trio CaMK1β CHK1 QIK Sev RGC Trio RAD53 NIM1 SIK Lmr3 DYRK3 ANPα QIK Ror HSER Alpha CAMK CAMK1CaMK4CaMK1δ ABC1 Lmr2 DYRK4 RIOK1 STK33STK33 NuaK CHK1 Lmr1 DYRK2 AlphaK3 SgK495 LKB QSK Met AlphaK2 CaMK1γCaMK1α CDK AlphaK1 TrblCAMK-Unique Ret KDR Trb2 CASKSgK495 NIM1 FLT4 TTBK1 Trb3 NuaK1 FAK FLT1 TTBK eEF2KChaK CAMK2 TTBK2 CK1 Trb1 MLCKVACAMKL NuaK2 Chak1 CASK CaMK2β Lkb1 IRR ULK1ULK2 Wee1 PDGFR InSR TLK1 smMLCK CaMK2γCaMK2α Fused MYT1 Chak2 TTN TSSK DAPK IGF1R ULK3 Wee1B VRK3VRK EEF2K SgK085 CaMK2δ ULK4 TLK2 CK1CK1ε Musk FGFR4 caMLCKskMLCK SgK223 SgK069 VRK2 CK1γ2 DRAK2 ALK FGFR3 IKKβ PRPK VRK1 CK1δ TSSK3 DRAK1 MAPKAPK FGFR2 SgK493 CK1γ3 TSSK4 IKKα IKKε SgK269 ULK SgK110SBK CK1γ1 TSSK2 DAPK1 FGFR1 SgK496 WEE CK1α2 Lmr TBK1 TLK CK1α SSTKTSSK1 DAPK3DAPK2 Fes NKF1 MK2 Fer IKK NKF3 PIK3R4NRBP1 MK5 VEGFR RNAseL PINK1 Bud32SgK493 MAPKAPK3 SgK196 Dusty NRBP2 HER4 NRBP HER3 SgK396 NKF2 VPS15 MAPKAPK2 InsR Other-Unique MNKMAPKAPK5 HER2 GCN2 KIS SgK307 MEK1/MAP2K1MEK2/MAP2K2 NIK EGFR GCN2 PKR KIS Other TOPKNKF5 PEK PBK SEK1/MAP2K4 STE-UniqueCOT SgK071 SgK424 STE TK FGFR EphB6 HRI Aur BUB SlobTTK STE7 GCN2~b MNK2MNK1 CMGC AurC/Aur3 MKK6/MAP2K6 EphB4 PEK Bub1 MOS MAP2K5 SgK071Haspin TBCK EphB3 PERK/PEK AurA/Aur2AurB/Aur1 Slob TTK MAP2K7 Atypical Fer BubR1 CDC7 MKK3/MAP2K3 EphB2 NAK IRE WNK EphB1 MAP3K7 NKF4 STE11MEKK3/MAP3K3 EphA8 PLK WNK4 EGFR EphA7 BIKE CAMKKHaspin MOS WNK1 RSKL1RSKL2 ASK/MAP3K5MEKK6/MAP3K6 EphA6 MPSK1 SCY1 WNK3 SGK1SGK3 MEKK2/MAP3K2 EphA5 TBCK MAP3K4 GAK IRE2 WNK2 YANK3 SGK2 MEKK1/MAP3K1 EphA4 AAK1 IRE1 CDC7 YANK1 RSKL MAP3K8 EphA3 NEK PLK4 SGK TAO1 CLIK1LCLIK1 YANK2YANK TAO2 EphA2 PLK2 SgK494 LOK EphA10 PLK3 RSKR SLK TAO3 Eph EphA1 Nek9 PLK1 AGC TAO Nek8 Nek6 SCYL2 PKN2/PRK2PKN PRKX SLK CAMKK-Meta Nek7 SCYL3 PDK1 PKA HPK1 DDR2 Nek3 PKG PRKY MST3 STLK3 DDR1 Nek10 Nek4 SCYL1 PKN3 PKAβ CAMKK1 Nek5 PKN1/PRK1PDK1 PKG2 STE20FRAY KHS KHS2GCK Nek11 PKG1 PKAγ MST4 YSK OSR1 CTK CAMKK2 Nek2Nek1 Akt PKAα NDR YSK1 KHS1 CSK MAST DDR Akt1/PKBαAkt3/PKBγ NinaCPAKB CCK4/PTK7 NDR2 STLK PAK5 LATS1 MSN Csk Akt2/PKBβ MASTL NDR1 TNIK/ZC2 MST MYO3B PAK6 Arg MAST1MAST2 PAKA CCK4 Abl GRK LATS2 DMPK MINK/ZC3NRK/ZC4 PAK4 CAMK MAST3MAST4 STLK5STLK6MYO3A Abl ZAK HGK/ZC1 CRIK PAK2 MST2 ZAK TAK1 BARK RSK ROCK MST1 PAK3 TAK1 BARK2/GRK3 PKC ROCK1 PAK1 MLK4 ROCK2 MLK3 BARK1/GRK2 MLK MLK2 MSK GRK GEK MLK MLK1 GRK7 RSKp70 PKCh GRK6 MSK1MSK2 PKCi DMPK2 LZK LZK GRK4 PKCd PKCη MRCKβMRCKα DLK p70S6K RHODK/GRK1GRK5 PKCε DMPK ILK RSKp90p70S6Kβ PKCι PKCa HH498 ILK PKCδ PKCζ HH498 RSK2 STKR RSK3 PKCθ PKCγ TKL STKR2 RSK4 PKCα TGFβR2 RSK1/p90RSK PKCβ MISR2 BMPR2 ACtR2B LISK ACtR2 STKR1 TGFβR1 BMPR1B BMPR1A TESK ALK7

Figure 1. Three modes of kinome visualization. (A) A ‘Tree’ plot generated by Coral in which log2 RNA fold change in encoded in branch color and node color, and RNA RPKM values are encoded in node size. (B) A zoomed in image of a ‘Circle’ plot generated by Coral that depicts kinase group in node color and RNA RPKM values in node size. (C) A ‘Force’ plot generated by Coral depicting the same data as in panel B.

2 bioRxiv preprint doi: https://doi.org/10.1101/330274; this version posted May 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

RESULTS Coral is a highly customizable kinome visualization tool different classes of kinases and can also be applied to high- that provides unprecedented flexibility in terms of attribute light kinases of interest such as targets of kinase inhibitors. encoding and visualization modalities, allowing for the The traditional and network kinome structures can be creation of high-resolution figures through a user-friendly used to highlight different features of data depending on the platform. application. For example, the Tree layout may be useful for Coral offers multiple modes of data input and supports a sharing data among audiences familiar with the historically variety of kinase identifiers. The user can supply both quali- used phylogenetic tree, while the network layouts are tative and quantitative data by selecting from pre-populated useful when there is a need to explicitly include family and pulldown menus or by pasting information from common subfamily delineations and highlight the hierarchy of the data sources such as spreadsheet editors. Coral inputs and kinase classifications. outputs are compatible with multiple identifiers including With the constantly growing wealth of human kinase UniProt, ENSEMBL, Entrez and HGNC, as well as an alphanu- studies, Coral fills a need for easily-generated, customiz- meric version of the names displayed in the original kinome able, high-resolution images for the intuitive visualization tree, referred to as their CoralID. of kinase data in the broader context of the human kinome. Data can be encoded in branch color, node color, node size, and any combination thereof. Coral supports categor- METHODS ical, sequential, and divergent color schemes by providing Coral was developed using R and Javascript. several color-blind friendly palettes, as well as the option to create your own. This allows for straightforward incorpo- The R package shiny (Chang, et al., 2017) and its extensions ration of multiple types of data within a single figure, using shinydashboard (Chang and Ribeiro, 2017), shinyBS (Bailey, 2015) intuitive color schemes and automatically generated legends and shinyWidgets (Perrier and Meyer, 2018) were used for the web for ease of interpretation. framework. Coral features three modalities of visualization. First, The R packages readr (Wickham, et al., 2017) and rsvg (Ooms, 2017) through the use of a newly rendered scalable vector graphics were used for data manipulation and rendering the SVG elements. (SVG) file, Coral outputs high-resolution images with data RColorBrewer (Neuwirth, 2014) was utilized for color palettes. encoded in a kinome tree based on the one created by Cell Signaling Technology (Figure 1A). Second, data can be The Circle and Force layouts were written using the D3.js library depicted in a circular radial kinase network with nodes for (Bostock, et al., 2011). kinases, groups, families, and subfamilies ( ). Finally, Figure 1B The kinome tree was obtained courtesy of Cell Signaling Technol- kinase attributes can be displayed in a dynamic force-directed ogy Inc. (www.cellsignal.com), and manually redrawn using vector network that uses the same underlying network structure as graphics in Adobe Illustrator. the circle plot (Figure 1C). All plots can be downloaded as high-resolution vector graphic files suitable for publication AUTHOR CONTRIBUTIONS without the need for further refinement in graphic editing software. In addition, Coral provides advanced options Conceptualization: D.H.P. for customizing features including titles, legends, fonts, Software: D.H.P., E.M.D., M.E.B, B.A.A., I.J.R., and K.S.M. transparencies, and node highlights. Users can also browse a Writing: K.S.M. and D.H.P. searchable and sortable table of kinases and their associated Visualization: E.M.D. attributes. Supervision: D.H.P. Coral was designed with user experience in mind. Each Resources: D.H.P., S.M.G, and J.H. plot responds to user input, updates in real time, and features drag and zoom capabilities. Individual nodes are ACKNOWLEDGEMENTS also interactive and either include links to UNIPROT pages or We thank Danielle Swaney, Emily Cousins, and Craig Wenger for expand when hovered above making it easier to read text and helpful conversations and software testing. visualize colors for individual nodes. Features are extensively documented in the Coral information pages which include FUNDING both example data and example outputs for each feature to help familiarize users with its many options. D.H.P. is supported by the National Institutes of Health (NIH), National Human Genome Research Institute (NHGRI) grant R00HG008662 and a Junior Faculty Development Award from IBM DISCUSSION and the UNC Provost’s office.

Due to its flexibility and wealth of customizable features, K.S.M. is supported in part by a grant from the National Institute of Coral can potentially be applied to many areas of study within General Medical Sciences under award 5T32 GM007092. human kinome research. Quantitative data can be presented through branch color, node color, and node sizes and can fea- M.E.B. and S.M.G. are supported by the National Institute of Diabetes ture sequential information (e.g. transcript or protein levels, and Digestive and Kidney Diseases (NIDDK) grant U24DK116204. kinase activity, or -log p-values) as well as divergent values S.M.G. is supported by the National Cancer Institute (NCI) grant (e.g. log2 fold-change). Qualitative data such as built-in R01CA177993. kinase family assignments can easily differentiate between

3 bioRxiv preprint doi: https://doi.org/10.1101/330274; this version posted May 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

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