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a sequence-specificity atlas of the kinase world · e oline atypical pbk cygf cygd hser anpb anpa e...

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  • A Sequence-Specificity Atlas of the Kinase World · e oline Atypical PBK CYGF CYGD HSER ANPb ANPa e ... Lck HCK Lyn Fgr Src Yes Fyn Srm Brk Abl2 Abl ITK Tec TXK BMX BTK FAK PYK2 Syk
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O Negative Proline Atypical Positive PBK HSER ANPb ANPa CYGF CYGD ILK BMPR1B BMPR1A TGFbR1 ALK4 ALK7 ALK2 ALK1 TGFbR2 ACTR2 ACTR2B BMPR2 MISR2 TESK2 TESK1 LIMK1 LIMK2 HH498 MAP3K7 2 ZAK MAP3K10 MLK4 MAP3K9 MAP3K11 DLK MAP3K13 ARAF BRAF RAF1 KSR2 KSR1 LRRK2 LRRK1 RIPK1 RIPK3 RIPK2 ANKRD3 SgK288 MLKL IRAK4 IRAK2 IRAK1 IRAK3 Wnk3 Wnk1 Wnk2 Wnk4 NRBP1 SCYL2 SCYL1 SCYL3 PIK3R4 Slob SgK424 SgK307 SgK496 NRBP2 MOS CK1gamma3 CK1gamma1 CK1gamma2 CK1delta TTBK1 TTBK2 VRK3 VRK2 VRK1 CK1epsilon CK1alpha CK1alpha2 PRPK CLIK1L CLIK1 SgK071 TTK KIS NEK10 NEK7 NEK6 NEK2 NEK11 NEK4 NEK3 NEK5 NEK1 NEK8 NEK9 MPSK1 GAK BIKE AAK1 HRI GCN2 1 EIF2AK2 PEK MYT1 Wee1 Wee1B RNAseL IRE2 IRE1 CDC7 TBCK PINK1 SgK269 SgK223 SBK SgK069 SgK110 SgK493 Haspin SgK196 SgK396 BUB1 BUBR1 RIOK2 RIOK3 RIOK1 TIF1beta TIF1alpha TIF1gamma BrdT Brd4 Brd2 Brd3 ADCK2 ADCK4 ADCK3 ADCK5 ADCK1 PDHK2 PDHK4 BCKDK PDHK1 PDHK3 DNAPK SMG1 TRRAP mTOR ATM ATR AlphaK3 Chak2 Chak1 eEF2K AlphaK2 AlphaK1 CTK Csk Fer Fes FRK BLK Lck HCK Lyn Fgr Src Yes Fyn Srm Brk Abl2 Abl ITK Tec TXK BMX BTK FAK PYK2 Syk ZAP70 EphA1 EphA2 EphA8 EphA3 EphA5 EphA4 EphA6 EphA7 EphB1 EphB2 EphB3 EphB4 EphA10 EphB6 Tie1 Tie2 PDGFRalpha PDGFRbeta FLT3 CSF1R Kit Ret FGFR4 FGFR3 FGFR2 FGFR1 FLT4 KDR FLT1 Ros ALK LTK IRR InsR IGF1R DDR2 DDR1 Musk TRKA TRKB TRKC ROR1 ROR2 RYK Sky Axl Mer Ron Met TNK2 TNK1 Tyk2 JAK1 JAK3 JAK2 ErbB3 ErbB4 ErbB2 EGFR CCK4 Lmr3 Lmr1 Lmr2 SuRTK106 Tyk2 2 JAK1 2 JAK2 2 JAK3 2 MAP4K1 MAP4K2 KHS2 MAP4K5 SLK LOK MYO3A MYO3B NRK MAP4K6 MAP4K4 TNIK MST3 MST4 YSK1 MST1 MST2 TAO1 TAO2 TAO3 PAK1 PAK3 PAK2 PAK6 PAK4 PAK5 OSR1 STLK3 STLK5 STLK6 MAP2K5 MAP2K1 MAP2K2 MAP2K7 MAP2K4 MAP2K6 MAP2K3 MAP3K8 MAP3K14 GCN2 2 MAP3K4 MAP3K6 MAP3K7 MAP3K5 MAP3K1 MAP3K8 2 MAP3K3 MAP3K2 CK2alpha CK2a2 CDK10 PITSLRE CDK9 CRK7 CHED CDK6 CDK4 CDK5 CDK1 CDK3 CDK2 PCTAIRE1 PCTAIRE2 PCTAIRE3 PFTAIRE1 PFTAIRE2 CDK7 CDK11 CDK8 CCRK MAPK6 MAPK4 MAPK15 MAPK1 MAPK3 MAPK7 NLK MAPK13 MAPK12 MAPK14 MAPK11 MAPK10 MAPK8 MAPK9 CDKL5 CDKL1 CDKL4 CDKL2 CDKL3 MOK ICK MAK GSK3beta GSK3alpha PRP4 DYRK1B DYRK1A DYRK4 DYRK2 HIPK4 HIPK2 HIPK1 HIPK3 CLK3 CLK2 CLK1 CLK4 SRPK1 SRPK2 MSSK1 DYRK3 CaMKKbeta TLK2 TLK1 IKKepsilon TBK1 AuroraA AuroraC AuroraB PLK4 PLK1 PLK3 PLK2 IKKalpha IKKbeta CaMKKalpha PDK1 PKAbeta PKAalpha PKAgamma PRKY PRKX PKG1cGKI PKG2cGKII RSK2 RSK1 RSK3 RSK4 p70S6K p70S6Kb MSK2 1 RSK5 PKBalpha PKBbeta PKBgamma SGK2 SGK1 SGK3 PKN3 PKN2 PKN1 PKCiota PKCzeta PKCdelta PKCtheta PKCeta PKCepsilon PKCalpha PKCbeta PKCgamma GRK3 GRK2 GRK6 GRK4 GRK5 GRK1 GRK7 LATS1 LATS2 CRIK NDR2 NDR1 ROCK1 ROCK2 DMPK1 DMPK2 MRCKb MRCKa MASTL MAST1 MAST4 MAST2 MAST3 SgK494 YANK3 YANK2 YANK1 RSKL1 RSKL2 ULK3 ULK2 ULK1 Fused ULK4 CHK2 PKD1 PKD3 PKD2 MSK1 2 MSK2 2 RSK4 2 RSK2 2 RSK3 2 RSK1 2 Mnk1 Mnk2 MAPKAPK5 MAPKAPK3 MAPKAPK2 PHKg2 PHKg1 CASK CaMKIIdelta CaMKIIalpha CaMKIIbeta CaMKIIgamma DCAMKL3 DCAMKL2 DCAMKL1 PSKH1 PSKH2 VACAMKL CaMKIV CaMKIbeta CaMKIgamma CaMKIalpha CaMKIdelta STK33 DAPK3 DAPK1 DAPK2 DRAK1 DRAK2 TTN smMLCK skMLCK caMLCK SgK085 Trio Trad Obscn 1 SPEG 1 SPEG 2 Obscn 2 HUNK MELK MARK1 MARK2 MARK3 MARK4 QSK QIK SIK NuaK2 NuaK1 AMPKa2 AMPKa1 BRSK1 BRSK2 LKB1 CHK1 SNRK NIM1 TSSK4 TSSK2 TSSK1 TSSK3 SSTK PASK Pim2 Pim3 Pim1 SgK495 Trb3 Trb1 Trb2 TK STE TKL CK1 CMGC AGC CAMK CDK MAPK Atypical Polo PKC Src MAP3K PIKK NEK TKL TK STE CK1 CMGC AGC CAMK MYT1 Wee1 Wee1B PIK3R4 SgK493 VRK1 VRK2 CK1γ2 CK1γ1 CK1γ3 PRPK Haspin SCYL2 SCYL1 SCYL3 SgK196 SgK396 Slob VRK3 MSK1 p70S6Kβ RSK3 PKCι PKCζ PKN3 RSK4 RSK1/p90RSK GRK4 GRK5 TLK2 PLK4 PLK3 PLK2 MRCKβ MRCKα GRK6 AurA/Aur2 TLK1 AurB/Aur1 AurC/Aur3 NDR1 NDR2 DMPK2 YANK2 YANK3 YANK1 SgK494 PDK1 BARK1/GRK2 BARK2/GRK3 GRK7 MAST3 MASTL MAST2 MAST4 MAST1 MSK2 Akt3/PKBγ SGK2 SGK1 SGK3 CRIK PKAα PKAβ PRKY PRKX PKG2 PKG1 PKAγ CAMKK1 CAMKK2 ULK1 ULK2 BIKE AAK1 SBK RSKL2 RSKL1 IKKε TBK1/NAK SgK069 SgK110 GAK MPSK1 MAP2K5 MAP2K7 OSR1 STLK3 STRAD/STLK5 STLK6 MKK3/MKK6 TAO3 PAK6 LOK SLK NIK GCN2~b TAO2 TAO1 PAK1 PAK2 PAK5/PAK7 PBK CDK8 CDK11 ERK7 ERK3 ERK4 CDKL5 ICK MAK CCRK CDK7 NLK CDKL1 CDKL4 CDKL2 CDKL3 CHED CRK7 CDK10 PITSLRE JNK2 CDK5 ERK2/p42MAPK ERK1/p44MAPK PCTAIRE3 PFTAIRE1 PFTAIRE2 CDK3 PCTAIRE1 PCTAIRE2 MOK SgK071 CLIK1L CLIK1 TTK KIS IRE1 IRE2 TBCK HRI GCN2 CDC7 MAP3K4 KHS1 KHS2 NRK/ZC4 MYO3B MST1 MST2 TNIK/ZC2 MINK/ZC3 MAP3K8 MEKK6/MAP3K6 RIPK3 LIMK2 TESK1 TSK2 ALK2 TGFβR2 RIPK2 HH498 TAK1 ARaf KSR KSR2 BMPR1B ALK7 ActR2 ActR2B ANKRD3 SgK288 ZAK ALK4 DLK LZK MLK2 MLK1 MLK3 LRRK1 LRRK2 SgK496 RIPK1 WNK3 WNK2 NRBP1 NRBP2 MEKK1/MAP3K1 MEKK2/MAP3K2 ASK/MAP3K5 MAP3K7 MLKL SgK307 SgK424 HSER ANPβ/NPR2 IRAK1 IRAK3 ULK3 ULK4 Fused MELK NIM1 SNRK SSTK TSSK3 TSSK1 AMPKα1 AMPKα2 BRSK1 BRSK2 ARK5 SNARK MARK4 QSK MARK3 QIK SIK MARK1 MARK2 CaMKIβ CaMKIγ RSK3~b PKD2/PKCμ HUNK DCAMKL3 CASK MAPKAPK5 VACAMKL PSKH1 PSKH2 MAPKAPK2 MAPKAPK3 MSK1~b MSK2~b RSK4~b TSSK2 TSSK4 Nek6 Nek7 Nek9 Nek11 Nek4 Nek3 Nek5 Nek10 STK33 MNK1 MNK2 PhKγ1 PhKγ2 PKD3/PKCν DCAMKL1 DCAMKL2 CaMKIV CaMKIIα CaMKIIδ CaMKIIβ CaMKIIγ RSK1~b RSK2~b PKD1 Trb1 Trb3 Trb2 SgK495 DRAK1 DAPK2 caMLCK SgK085 DAPK3 DRAK2 smMLCK TTN Trad Trio Obscn SPEG Obscn~b SPEG~b Chk1 PASK LKB1 SuRTK106 MOS Lmr1 Lmr2 Lmr3 Etk/BMX ITK BLK EphA8 TEC TXK HCK EphA7 EphA6 EphB3 EphA4 EphB1 EphA5 EphA10 EphB6 FRK Srm CSK CCK4/PTK7 DDR1 DDR2 MuSK Met Ron IRR ROR1 Tnk1 HER3 Jak3 PYK2/FAK2 RYK Ack Jak1 Tyk2 Jak2 HPK1 GCK MST3 YSK1 SgK223 SgK269 TTBK1 TTBK2 CaMKIα CaMKIδ PRP4 SRPK2 HIPK4 CLK3 CLK4 CLK2 CLK1 MSSK1 SRPK1 DYRK1B DYRK4 HIPK3 DYRK2 DYRK3 Bub1 BubR1 CK1α1 CK1α2 CK1δ CK1ε p70S6K PKCδ PKCθ RSK2 PKCγ PKCη PKCε PKCα PKCβ PLK1 RHOK/GRK1 DMPK ROCK1 ROCK2 PKN1/PRK1 PKN2/PRK2 LATS1 LATS2 Akt1/PKBα Akt2/PKBβ IKKα IKKβ SEK1/MAP2K4 PAK3 MEK1/MAP2K1 MEK2/MAP2K2 Tpl2/COT PAK4 CDK9 CDK4 CDK6 JNK1 JNK3 p38α p38β p38δ p38γ cdc2/CDK1 CDK2 MYO3A MST4 HGK/ZC1 LIMK1 ALK1 MISR2 BMPR2 ILK BMPR1A BRaf C-Raf/Raf1 TGFβR1 MLK4 WNK1 WNK4 MEKK3/MAP3K3 IRAK4 IRAK2 Chk2/Rad53 Nek2 Nek8 Nek1 DAPK1 skMLCK Pim1 Pim3 Pim2 EphA2 EphA1 Zap70/SRK Syk FAK PINK1 GSK3α GSK3β ERK5 CK2α2 CK2α1 RNAseL PKR PERK/PEK GUCY2D GUCY2F ANPα/NPR1 Jak1~b Tyk2~b Jak2~b Jak3~b BTK Fgr Lck Fyn Lyn Src Yes EphB4 EphB2 EphA3 Fer Brk Abl Abl2/Arg CTK FLT4 FLT3 Axl Mer FLT1/VEGFR1 ALK LTK IGF1R InsR TrkA FGFR2 EGFR HER2/ErbB2 HER4 KDR/VEGFR2 Fms/CSFR Kit FGFR3 FGFR1 FGFR4 PDGFRβ PDGFRα TrkB TrkC Tyro3/ Sky Ret Ros ROR2 Tie1 Tie2 Fes DYRK1A HIPK1 HIPK2 Atypical Protein Kinases Brd RIO ABC1 PIKK PDHK Alpha AlphaK1 AlphaK2 ChaK2 ChaK1 AlphaK3 Brd2 Brd3 Brd4 BrdT RIOK3 RIOK1 RIOK2 TIF1γ TIFα SMG1 ADCK1 ADCK5 ADCK3 ADCK4 ADCK2 PDHK2 PDHK3 PDHK1 PDHK4 EEF2K TIF1β DNAPK TRRAP BCKDK ATM ATR mTOR/FRAP The Human Kinome TIF1 Protein kinases are enzymes that mediate cellular decision processes by catalyzing the addition of a negatively charged phosphate group to protein substrates, which can subse- quently be recognized by phosphorylation-dependent binding domains in other proteins. e human genome encodes 518 protein kinases, which have been organized into a tree that represents evolutionary relationships. e substrate specificities of kinases are in part determined by the amino acid sequence of the phosphorylation sites, and comprehensively mapping the consensus sequence motif recognized by each kinase catalytic domain is thus crucial for understanding phosphorylation-mediated signaling networks. NetPhorest (http://netphorest.info) is a community resource that uses phylogenetic trees to organize data from both in vivo and in vitro experiments to derive sequence specificities for individual kinase or phosphorylation- dependent binding domains or families of closely related domains. is poster presents the specificities of kinases as sequence logo plots around a phylogenetic map of the human protein kinases. e height of a stack of letters represents the information content of a particular position relative to a phosphorylation site, and the height of the individual letters is proportional to the frequency of the amino acid residue in question. e serine, threonine, or tyrosine phosphoacceptor residues are placed at the center of each logo plot. Closely related kinases typically have similar substrate specificities; however, distantly related kinases may not have divergent substrate specificities. e compass summarizes the major trends of the specificity atlas in the center; for example, most kinases that prefer positively charged residues are located in the lower leſt-hand part of the phylogenetic map. Finding the Targets of the Human Kinome Poster authors: Martin Lee Miller, Søren Brunak, Lars Juhl Jensen, Michael B. Yaffe, Rune Linding Science Signaling coordinator: Nancy R. Gough Design and production: Lars Juhl Jensen, Rune Linding, Dave Comb, Aileen Taylor, Marcus Spiegler Copyeditor: Harry Jach Sponsored by Cell Signaling Technology, Inc. This poster accompanies the Science Signaling paper “Linear Motif Atlas for Phosphorylation-Dependent Signaling” by Martin Lee Miller, 1,2* Lars Juhl Jensen, 2,3* Francesca Diella, 3 Claus Jørgensen, 4 Michele Tinti, 5 Lei Li, 6 Marilyn Hsiung, 4 Sirlester A. Parker, 7 Jennifer Bordeaux, 7 Thomas Sicheritz-Ponten, 1 Marina Olhovsky, 4 Adrian Pasculescu, 4 Jes Alexander, 8 Stefan Knapp, 9 Nikolaj Blom, 1 Peer Bork, 2,10 Shawn Li, 6 Gianni Cesareni, 5 Tony Pawson, 4 Benjamin E. Turk, 7 Michael B. Yaffe, 8† Søren Brunak, 1,2† Rune Linding 4,8,11† 1 Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Lyngby, Denmark. 2 The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. 3 European Molecular Biology Laboratory, 69117 Heidelberg, Germany. 4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5. 5 University of Rome, Tor Vergata, 00133 Rome, Italy. 6 University of Western Ontario, London, Ontario, Canada N6A 5C1. 7 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. 8 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 9 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. 10 Max-Delbrück-Centre for Molecular Medicine, 13092 Berlin, Germany. 11 Cellular & Molecular Logic Team, The Institute of Cancer Research, London SW3 6JB, UK. * These authors contributed equally to this work. † To whom correspondence should be addressed. E-mail: [email protected] (S.B.), [email protected] (M.B.Y.), and [email protected] (R.L.) A Sequence-Specificity Atlas of the Kinase World © 2008 American Association for the Advancement of Science. All Rights Reserved. -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 A S G P K R K R S Q H K R Y K N Q R H T S G Pim2 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 L P T E S Q S LA G E S P S D L S T S Q E S P Q S S I E D Q S V D S P L S ATM/ATR -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 M G V L Q S V L H A G Q F S T P S V G T S Q L I E A I N V G F D T P T S Q P L G A P E A S L T S L N Q Q T G D V S A E G E M N R V A S P Q T G H K D F S L E K Q G P D S T F S A N P R G T L Q DNAPK -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 I S T V A K Q N K P T G E L N P R T V K Q S L Q S V G A H L P Q S Y T K R A L K R N S T V I L E R K T S L N G V S Y L A N P S V C I G I K R D V S A G S M I G D R E T V A K K L R S W A I T G E P V N H F A E P L G P L G F A AuroraB/AuroraC -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 L R T V P Q K K L P E S A R G K P S E Q N E K N Q T L S F K L Q S T P R G N Q S C A V K L R K R S T S T G A K R V G K T V L Q P I H S A E V P F N V G K L P N G D Q A K N T K E P S L Q E P A R AuroraA EIF2AK2 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 P M K I A N L S D I P Q R K L M E V G K N E R T D P S L M R K L P E D V T R M K I G F A L S H E A L P T K G F D T V Y E L R S T K N E T V G L P R Y F E D A R S T L L N P D R Y G K S T I M G V L E S R M G F R S D T E P D R S T V G K L L M G S T I E D R EphB3 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 E D N Y A D E mTOR -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 F N D G P R S T G L N P R T V F Q S G K E M Q T V I P S H L G R D T F E P Y V P K G F C L S T G T I P S V R H K F D Q V N R T T S F Y P I E P D R S G V K T A R S G D K F P S T D G I E P V L R S T V K I G F D A L P I L F D T V G P S -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 T D L R S E R E S H N E S V D T L S E V I N K L E D G Q S L E D A H P T I M E D L Y S A E V D F E D N P Q T Y S Q S V G M L P E L S T V N R P M Q E K N D P N Q E L P E D G N R A Tec family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 D S E S T L G P D E M P D E P S A E D N S E D A N S E D P S E V G D YT M K A Y L D V E S T N D E E M A L V P P D P S E P D E Syk family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 I L P V A S D I G E R T A H P S L K G Q E H S A L P K E I S L A T H Q I D S Y T S F G A L K D G P E D Y E G K T P V I A Y L P T V K I M P E T V L F E N P R K D V S I K L T V H F E P D K D R W A T I S P E D S T G JAK2/JAK3 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 E SG L K E K S D E R D S T E P G N D P E G D Y I A M T N S V A P I M Y N E S S G P L P V K G G K InsR/IGF1R -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 S E S E E S D E D E S E D T S G S E D G S D E T G S D E G S D E S D E S D E D E CK2 family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 K S P L S L P P G S T S G H K L E R P P A S K V L G S P K R S K S L P CDK1 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 S L P S E SS S P GT S H G T A P A R G P S Q H P S T R K P R L L CDK2/CDK3 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 H K R T M N P S I K P Q S V L M R Y P K H A D S A I L N A Q P R I H Y P M G F E A L S T S PY T R I F L A P I R S H T A P I L H N F S V G Y T R N K I H A S V K Q E T L A R K L D P S T Q R Y CDK4/CDK6 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 Y S R P I A L G I L P E V K H R S Y R K A E S P I G P Q F S V N K H I M N Q S K P R G L F P Q R T S V A K G Q F T Y L T S K I R T D H P H K L F N P Q S V Y E K L H G P T R V K H N E A Q S V Y S Q P L K I A T M K H A T R L L M H G F S D V W CDK7 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 R SS K RS R T S S K R K G R S PKC family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 R T P S K R T S K R T S PKA family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 K L S D E G P E S L R V N S T L E L P G D P L T S E S D T S K Q S L P L E V S E N P Q R S D I L T E V A P S S A K L D N A S PLK1 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 K N V E R G P L R A S G F S T P L G P S R L N Q T D A K S P R L T V G A P Q S E V P T L T S M R S V E L P F D N P R T E S G E P T V L D A S I G E Q T A L P S E L D R T V K P S G E S G R T P A MAPKAPK family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 E R V S E D E Q S D E T D P R T E S P E V A G D T S S T E N G V D S T L N Q D G V S G S E D Q S G GRK subfamily -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 L R A N P Q V D G T R S K V A K P Q E I S R Y Q P N E A K G D R S V T Q G A S F Y K R K L E V H G S Y R I F T K L N P S Y R S T F L Q R T G S K S T Q G V R G T V R S N I A M S L D A K G F R P S V L S K Q Y G E P P S T G F D M ROCK family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 L E S T D A G I N G F Q R S P L R L G D R A P S R H R L A T S G N P L V A R S C T S Y K W N M L V A R V A S T P D K Q E T D G L N S Q S V A T I R V N S I L K N E P S A S E G SGK family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 I L N F T V E S D H N G D Y I E S M S L S T D G E R N F V A N G E D R Q K H D A N S Y I K L F D T V S N E Y F E D S T A K I V L F E R D V Y N M P F R D V I K L H P T W A L G R D H K L Q F S E N P S T A G F K P Q R S E FLT3/CSF1R/Kit -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 V I K L R S T A H G E Q R T C D V S S P M L K F E A G T D Y V N M K Q E D S I G D S V F L M T L M A V T E T Q A P K D G M S Y T I L M R D W G P V M E T D V A Y D S W K T V A S P N M D A G T R V Y S R E A M C W T K L G P V D Y R I L E D S W Y P A R MAP2K3/4/6/7 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 P D S I E P SS T A P L G S A P L T S P L V A E P S A P E P A T SS JNK subfamily -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 P E P G V P R T P E S G V S P S T A L P D V L S P T S K E A L S V G T R P K R L S A P L S V G P G L P Q D V T S H R S A T P P A S S P A GSK3 subfamily -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 M R Y S H P R S T G E D V A S Q M F E A L I H D T K E A S V L N P S E Q R G D I K P R S V A D E L M D C H S T N E YT M L C Y D V H K F D V N S I P N E L M P V G H K R Y D T N P Y N L C Q T A P N T S V R P L K A S Y G T Met family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 S P SSS G PS T A L P S L T S A P G S P S P P S P SSS MAPK1/3/7/NLK -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 N R D L G E A S S P L N S A K E V G K G E A F S D V M A K S L R T R Q M L K C G E S A T N Q H T F S S T N L P S Y F I H A E T S V C Y S N M F E D P A G I K L Q V P S T Y V N G D R S A I T P N I A T D E R Q L H G D A F T S Y PDK1 -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 P K R E S T G A G E N P G E D S G V YV D A T G T Q K I V P P S VG P Abl family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 F G R K R S A I S K A R G S T L V K E R H Q S T V G P A R Y V S H A G L K R I L A R V T S I K L Q A R G H E Q T A S L G S N E P R V E G A Q A P T K S L P A PKGcGK family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 R P G S R S Y L G D A S E R L Q E K R S K S W A G P R Q A L K R S P K D M L G R T S E D L S V R N D G P E S G K N R I P S P R S G F E D S E D L F P RSK family -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 H R I L M R T S R L AMPK subfamily CDK5 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 KT S P Q R K R H K K H R -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 Y W V F M I L M R H K R A M S R Q T H L N T S W C M L F Y I H W C Y R T S CHK2 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 D ET D E S Y T D E Y S F Y E T D S G D S A T A GT S CK1 family LKB1 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 A S P Y F W M W Y F C T V L I M R T C W P T DMPK family -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 L R L R R L T S L V -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 R C K P R V Q T S L R C P K G A S T Y R T S R G T S A P P D R S T ICK -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 N P D E P N D E G S N D E P T V I D E Y T Y V L I F I Y F W P M Y I L V F V P EGFR -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 C T Y F I V D L E YC Y Q A D E N I Y D V E H F Y L I V P EphA4 -7 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 R R H K R S R CLK family -6 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 Y K R K RS T T S M V L I W F N S G P PKB family -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 W H K R RQ H K R W Q K N Y R H T S Pim1 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 Q T N H K R R K Y S W K H R K S H L Y R T Y T S H T N C S R p70S6K subfamily -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 R R S W H K R V P S T H R R T S W I F L Y PAK2 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 R N G W Q S K R H S Y R Y K R T S C F L S Y M V I W V S Y C A L Y F W S PAK4 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 S T N D R G Y P N Q H G W Y S T Q P H N G T C W I M L C T S K R W S T N H P K R T S N K R TNIK -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 K R K N Q K H W R W T F K H R Y K N Y H R T R I F Y L W M T G N H K R H K R N H K R SLK -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 G S Y W M H T Q A W Y Y H M R K G N T C I W L M Q N H R K P A T S K R P K R MST1 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 Q R R N G C N R A H W Y Y H M R N G T R Y T W C L V M T G K R K R A T H G K R MST4 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 S I V L P G T M Q T S P F MAPK14 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 T E S D G N T S D E C T S H N E D T S L R M N Q D W W TLK1/TLK2 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 A Y T P A K T M S I V L T M S I A L V T S H R K E Q K R G H L M K C W T S Y W I F L M V I A V M M W Y F M W Y V F Y W P M F PKD family -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 W F W Y G W M L F T S L V T S M I H T S R NEK2 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 C K Q N S T R Q K R N S D E S N D E K R T S M S TGFbR2 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 G D E G D E E L T V I Y N D E A Q G E W Y F V I L Lck -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 P E N P E N T S Y G T P S D E T P S D E T P S D E T P S D E Y L E Y M F I V P E Y D Y L M F I V E PDGFR family -7 -6 -5 -4 -3 -2 -1 0 +1 +2 +3 +4 +5 +6 +7 K R S I K Y A R F L Q S E L R H G Q V K P S T R Y M I P A S R Q K R E D A T S I H T K V F L I K L R E Q S T D P R E D S E K S D L R I G Q S A P S L CaMKIIα/δ -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 R W Y F K K R N M Q K L F Q M T S Y L M V I F T E I S D T S L M I K W Y K F CaMKIIβ

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Page 1: A Sequence-Specificity Atlas of the Kinase World · e oline Atypical PBK CYGF CYGD HSER ANPb ANPa e ... Lck HCK Lyn Fgr Src Yes Fyn Srm Brk Abl2 Abl ITK Tec TXK BMX BTK FAK PYK2 Syk

O

Negative

Proline

Atypical

Positive

PB

K

HS

ER

AN

Pb

AN

Pa

CY

GF

CY

GD

ILK

BM

PR

1B

BM

PR

1A

TG

FbR

1A

LK

4

ALK

7

ALK

2A

LK

1

TG

FbR

2A

CT

R2

AC

TR

2B

BM

PR

2M

ISR

2

TE

SK

2TE

SK

1LI

MK

1LI

MK

2

HH

498

MAP3K

7 2

ZAK

MAP3K

10

MLK

4M

AP3K9

MAP3K

11DLK

MAP3K

13

AR

AF

BR

AF

RAF1

KS

R2

KS

R1

LRR

K2

LRR

K1

RIP

K1

RIP

K3

RIP

K2

AN

KR

D3

SgK

288

MLK

LIR

AK

4IR

AK

2IR

AK

1IR

AK

3

Wnk3

Wnk1

Wnk2

Wnk4

NR

BP

1

SC

YL2

SC

YL1

SC

YL3

PIK

3R

4S

lob

SgK

424

SgK

307

SgK

496

NR

BP

2

MO

S

CK

1gam

ma3

CK

1gam

ma1

CK

1gam

ma2

CK

1delta

TT

BK

1T

TB

K2

VR

K3

VR

K2

VR

K1

CK

1epsilo

nC

K1alp

ha

CK

1alp

ha2

PRPK

CLIK

1LC

LIK1

SgK

071TTKKIS

NE

K10

NE

K7

NE

K6

NE

K2

NE

K11

NE

K4

NE

K3

NE

K5

NE

K1N

EK

8N

EK

9MP

SK

1G

AK

BIK

EA

AK

1

HR

IG

CN

2 1E

IF2A

K2

PE

K

MYT1

Wee1

Wee1BR

NAseL

IRE2

IRE1

CD

C7

TB

CK

PIN

K1

SgK

269

SgK

223

SB

KS

gK

069

SgK

110

SgK

493

Hasp

inS

gK

196

SgK

396

BU

B1

BU

BR

1

RIOK2

RIOK3

RIOK1

TIF1beta

TIF1alpha

TIF1gamma

BrdT

Brd4

Brd2

Brd3

ADCK2

ADCK4

ADCK3

ADCK5

ADCK1

PDHK2

PDHK4

BCKDK

PDHK1

PDHK3

DNAPK

SMG

1

TRRAP

mTO

R

ATM

ATR

AlphaK3

Chak2

Chak1

eEF2K

AlphaK2

AlphaK1

CTK

Csk

Fer

Fes

FRK

BLKLckHCK

LynFgr

SrcYes

Fyn

SrmBrk

Abl2

Abl

ITKTecTXK

BMX

BTK

FAK

PYK2Syk

ZAP70

EphA1

EphA2

EphA8

EphA3

EphA5EphA4EphA6

EphA7EphB1

EphB2EphB3EphB4

EphA10

EphB6

Tie1Tie2PDGFRalpha

PDGFRbeta

FLT3

CSF1R

Kit

RetFGFR4

FGFR3

FGFR2FGFR1

FLT4

KDRFLT1

RosALKLTKIRRInsRIGF1RDDR2DDR1

MuskTRKATRKBTRKC

ROR1ROR2

RYK

SkyAxlMer

RonMet

TNK2TNK1Tyk2JAK1JAK3JAK2ErbB3ErbB4ErbB2EGFR

CCK4Lmr3Lmr1Lmr2SuRTK106

Tyk2 2JAK1 2JAK2 2JAK3 2

MAP4K1MAP4K2KHS2MAP4K5

SLKLOK

MYO3AMYO3BNRKMAP4K6

MAP4K4

TNIK

MST3MST4

YSK1

MST1MST2

TAO1TAO2

TAO3

PAK1PAK3

PAK2PAK6PAK4PAK5OSR1

STLK3STLK5

STLK6MAP2K5

MAP2K1

MAP2K2

MAP2K7

MAP2K4

MAP2K6

MAP2K3

MAP3K8

MAP3K14

GCN2 2

MAP3K4

MAP3K6

MAP3K7

MAP3K5

MAP3K1

MAP3K8 2

MAP3K3

MAP3K2

CK2alpha

CK2a2

CDK10

PITS

LRE

CD

K9

CR

K7

CH

EDC

DK6

CD

K4

CD

K5

CD

K1

CD

K3

CD

K2PC

TA

IRE

1

PC

TA

IRE

2P

CTA

IRE

3P

FTA

IRE

1

PFTA

IRE

2

CD

K7

CD

K11

CD

K8

CC

RK

MA

PK

6

MA

PK

4

MA

PK

15

MA

PK

1

MA

PK

3

MA

PK

7

NLKM

AP

K13

MA

PK

12

MA

PK

14

MA

PK

11

MA

PK

10

MA

PK

8M

AP

K9

CD

KL5

CD

KL1

CD

KL4

CD

KL2

CD

KL3

MO

KIC

KM

AK

GS

K3beta

GS

K3alp

ha

PR

P4

DY

RK

1B

DY

RK

1A

DY

RK

4D

YR

K2

HIP

K4

HIP

K2

HIP

K1

HIP

K3

CLK

3C

LK

2C

LK

1C

LK

4

SR

PK

1

SR

PK

2M

SS

K1

DY

RK

3

CaM

KK

beta

TLK

2T

LK

1

IKK

epsi

lon

TB

K1

Auro

raA

Auro

raC

Auro

raB

PLK

4P

LK

1P

LK

3P

LK

2

IKK

alp

ha

IKK

beta

CaM

KK

alp

haPD

K1

PK

Abeta

PK

Aalp

ha

PK

Agam

ma

PR

KY

PR

KX

PK

G1cG

KI

PK

G2cG

KII

RSK2

RSK1

RSK3

RSK4

p70S

6K

p70S

6Kb

MSK2

1

RSK5

PKBalph

a

PKBbeta

PKBgam

maSG

K2

SGK1

SGK3

PKN3PKN2

PKN1

PKCiota

PKCzeta

PKCdelta

PKCtheta

PKCeta

PKCepsilon

PKCalpha

PKCbeta

PKCgamm

a

GR

K3

GR

K2GR

K6

GR

K4

GR

K5

GR

K1

GR

K7

LATS

1

LATS

2

CR

IK

ND

R2

ND

R1

RO

CK

1

RO

CK

2

DM

PK

1

DM

PK

2

MR

CK

b

MR

CK

a

MA

ST

L

MA

ST

1

MA

ST

4M

AS

T2

MA

ST

3

SgK

494

YA

NK

3

YA

NK

2

YA

NK

1

RS

KL1

RS

KL2

ULK3ULK2ULK1

Fused

ULK4

CHK2

PKD1PKD3

PKD2

MSK1 2MSK2 2RSK4 2

RSK2 2

RSK3 2RSK1 2

Mnk1Mnk2

MAPKAPK5MAPKAPK3MAPKAPK2

PHKg2

PHKg1

CASK

CaMKIIdelta

CaMKIIalpha

CaMKIIbeta

CaMKIIgamma

DCAMKL3

DCAMKL2

DCAMKL1

PSKH1

PSKH2

VACAMKL

CaMKIV

CaMKIbeta

CaMKIgamma

CaMKIalpha

CaMKIdelta

STK33

DAPK3DAPK1

DAPK2

DRAK1DRAK2

TTNsmMLCKskMLCKcaMLCKSgK085

TrioTradObscn 1

SPEG 1SPEG 2

Obscn 2

HUNKMELK

MARK1MARK2

MARK3MARK4

QSKQIKSIK

NuaK2NuaK1

AMPKa2AMPKa1BRSK1BRSK2

LKB1CHK1

SNRKNIM1TSSK4TSSK2TSSK1TSSK3SSTK

PASKPim2Pim3Pim1

SgK495Trb3Trb1Trb2

TK

STE

TKL

CK1

CMGCAGC

CAMK

CDK

MAPK

Atypical

Polo

PKC

Src

MAP3K

PIKK NEK

TKLTK

STE

CK1

CMGC

AGC

CAMK

MYT1Wee1Wee1B

PIK3R4

SgK493

VRK1VRK2

CK1γ2

CK1γ1CK1γ3

PRPK

Haspin

SCYL2SCYL1SCYL3

SgK196

SgK396Slob

VRK3

MSK1

p70S6Kβ

RSK3

PKCιPKCζ

PKN3

RSK4

RSK1/p90RSK

GRK4

GRK5

TLK2

PLK4

PLK3

PLK2

MRCKβ

MRCKα

GRK6

AurA/Aur2

TLK1

AurB/Aur1AurC/Aur3

NDR1NDR2

DMPK2

YANK2YANK3

YANK1

SgK494

PDK1

BARK1/GRK2BARK2/GRK3

GRK7

MAST3MASTL

MAST2

MAST4 MAST1

MSK2

Akt3/PKBγ

SGK2SGK1SGK3

CRIK

PKAαPKAβ

PRKYPRKX

PKG2PKG1

PKAγ

CAMKK1CAMKK2

ULK1

ULK2

BIKE

AAK1

SBK

RSKL2RSKL1

IKKεTBK1/NAK

SgK069SgK110

GAK

MPSK1

MAP2K5

MAP2K7

OSR1

STLK3

STRAD/STLK5

STLK6

MKK3/MKK6

TAO3

PAK6

LOKSLK

NIK

GCN2~b

TAO2TAO1

PAK1

PAK2PAK5/PAK7

PBK

CDK8 CDK11

ERK7

ERK3ERK4

CDKL5

ICKMAK

CCRK

CDK7

NLK

CDKL1CDKL4

CDKL2CDKL3

CHED

CRK7

CDK10

PITSLREJNK2

CDK5

ERK2/p42MAPK

ERK1/p44MAPK

PCTAIRE3

PFTAIRE1PFTAIRE2

CDK3

PCTAIRE1

PCTAIRE2

MOK

SgK071

CLIK1LCLIK1

TTKKIS

IRE1IRE2 TBCK

HRI

GCN2

CDC7

MAP3K4

KHS1KHS2

NRK/ZC4

MYO3B

MST1MST2

TNIK/ZC2

MINK/ZC3

MAP3K8

MEKK6/MAP3K6

RIPK3

LIMK2 TESK1TSK2

ALK2

TGFβR2

RIPK2

HH498TAK1

ARaf

KSR KSR2

BMPR1BALK7

ActR2ActR2B

ANKRD3 SgK288

ZAK

ALK4

DLKLZK

MLK2

MLK1

MLK3

LRRK1LRRK2

SgK496

RIPK1

WNK3

WNK2NRBP1 NRBP2

MEKK1/MAP3K1

MEKK2/MAP3K2

ASK/MAP3K5

MAP3K7

MLKL

SgK307

SgK424

HSER

ANPβ/NPR2

IRAK1IRAK3

ULK3

ULK4Fused

MELK

NIM1

SNRKSSTK

TSSK3TSSK1

AMPKα1AMPKα2 BRSK1

BRSK2

ARK5SNARK

MARK4

QSK

MARK3

QIKSIK

MARK1MARK2

CaMKIβ

CaMKIγ

RSK3~b

PKD2/PKCμ

HUNK

DCAMKL3

CASK

MAPKAPK5

VACAMKL

PSKH1PSKH2

MAPKAPK2

MAPKAPK3

MSK1~bMSK2~b

RSK4~b

TSSK2

TSSK4

Nek6Nek7

Nek9

Nek11

Nek4

Nek3

Nek5

Nek10

STK33

MNK1MNK2

PhKγ1PhKγ2

PKD3/PKCν DCAMKL1DCAMKL2

CaMKIV

CaMKIIαCaMKIIδ

CaMKIIβCaMKIIγ

RSK1~b

RSK2~b

PKD1

Trb1

Trb3

Trb2

SgK495

DRAK1

DAPK2caMLCK

SgK085

DAPK3

DRAK2

smMLCK

TTN

TradTrio

Obscn

SPEG

Obscn~bSPEG~b

Chk1

PASKLKB1

SuRTK106

MOS

Lmr1Lmr2

Lmr3

Etk/BMX

ITK

BLK

EphA8

TECTXK

HCK

EphA7

EphA6

EphB3

EphA4

EphB1EphA5

EphA10

EphB6FRK

Srm

CSK

CCK4/PTK7

DDR1DDR2

MuSK

MetRon

IRR

ROR1

Tnk1

HER3Jak3

PYK2/FAK2

RYK

AckJak1

Tyk2Jak2

HPK1GCK

MST3

YSK1

SgK223SgK269

TTBK1TTBK2

CaMKIαCaMKIδ

PRP4

SRPK2

HIPK4

CLK3

CLK4

CLK2CLK1

MSSK1

SRPK1

DYRK1B

DYRK4

HIPK3

DYRK2DYRK3

Bub1

BubR1

CK1α1

CK1α2

CK1δ

CK1ε

p70S6K

PKCδPKCθ

RSK2

PKCγ

PKCηPKCε

PKCα

PKCβ

PLK1

RHOK/GRK1

DMPK

ROCK1ROCK2

PKN1/PRK1PKN2/PRK2 LATS1

LATS2

Akt1/PKBαAkt2/PKBβ

IKKα

IKKβ

SEK1/MAP2K4

PAK3

MEK1/MAP2K1MEK2/MAP2K2

Tpl2/COT

PAK4

CDK9

CDK4CDK6

JNK1JNK3

p38αp38β

p38δp38γ

cdc2/CDK1

CDK2

MYO3A

MST4

HGK/ZC1

LIMK1

ALK1

MISR2BMPR2

ILK BMPR1A

BRafC-Raf/Raf1 TGFβR1

MLK4

WNK1

WNK4

MEKK3/MAP3K3

IRAK4

IRAK2

Chk2/Rad53

Nek2

Nek8

Nek1

DAPK1

skMLCK

Pim1

Pim3

Pim2

EphA2

EphA1Zap70/SRKSyk

FAK

PINK1

GSK3αGSK3β

ERK5

CK2α2CK2α1

RNAseL

PKRPERK/PEK

GUCY2D

GUCY2F

ANPα/NPR1Jak1~b

Tyk2~bJak2~b

Jak3~b

BTK

FgrLck

FynLyn

SrcYes EphB4

EphB2

EphA3

Fer

Brk

AblAbl2/Arg

CTK

FLT4

FLT3Axl

Mer

FLT1/VEGFR1

ALKLTK

IGF1RInsR

TrkA

FGFR2

EGFR HER2/ErbB2

HER4

KDR/VEGFR2Fms/CSFR

Kit

FGFR3

FGFR1FGFR4

PDGFRβPDGFRα

TrkB

TrkC

Tyro3/Sky

Ret

Ros

ROR2

Tie1Tie2

Fes

DYRK1A

HIPK1

HIPK2

Atypical Protein Kinases

Brd

RIO

ABC1

PIKK

PDHK

Alpha

AlphaK1 AlphaK2

ChaK2ChaK1

AlphaK3

Brd2 Brd3

Brd4

BrdT

RIOK3 RIOK1

RIOK2

TIF1γ TIFα

SMG1

ADCK1

ADCK5 ADCK3 ADCK4

ADCK2

PDHK2 PDHK3PDHK1

PDHK4

EEF2K

TIF1β

DNAPK

TRRAP

BCKDK

ATMATR

mTOR/FRAP

The Human Kinome

TIF1

Protein kinases are enzymes that mediate cellular decision processes by catalyzing the addition of a negatively charged phosphate group to protein substrates, which can subse-quently be recognized by phosphorylation-dependent binding domains in other proteins. �e human genome encodes 518 protein kinases, which have been organized into a tree that represents evolutionary relationships. �e substrate speci�cities of kinases are in part determined by the amino acid sequence of the phosphorylation sites, and comprehensively mapping the consensus sequence motif recognized by each kinase catalytic domain is thus crucial for understanding phosphorylation-mediated signaling networks. NetPhorest (http://netphorest.info) is a community resource that uses phylogenetic trees to organize data from both in vivo and in vitro experiments to derive sequence speci�cities for individual kinase or phosphorylation-

dependent binding domains or families of closely related domains. �is poster presents the speci�cities of kinases as sequence logo plots around a phylogenetic map of the human protein kinases. �e height of a stack of letters represents the information content of a particular position relative to a phosphorylation site, and the height of the individual letters is proportional to the frequency of the amino acid residue in question. �e serine, threonine, or tyrosine phosphoacceptor residues are placed at the center of each logo plot. Closely related kinases typically have similar substrate speci�cities; however, distantly related kinases may not have divergent substrate speci�cities. �e compass summarizes the major trends of the speci�city atlas in the center; for example, most kinases that prefer positively charged residues are located in the lower le�-hand part of the phylogenetic map.

Finding the Targets of the Human KinomePoster authors: Martin Lee Miller, Søren Brunak, Lars Juhl Jensen, Michael B. Yaffe, Rune LindingScience Signaling coordinator: Nancy R. GoughDesign and production: Lars Juhl Jensen, Rune Linding, Dave Comb, Aileen Taylor, Marcus SpieglerCopyeditor: Harry JachSponsored by Cell Signaling Technology, Inc.This poster accompanies the Science Signaling paper “Linear Motif Atlas for Phosphorylation-Dependent Signaling” by Martin Lee Miller,1,2* Lars Juhl Jensen,2,3* Francesca Diella,3 Claus Jørgensen,4 Michele Tinti,5 Lei Li,6 Marilyn Hsiung,4 Sirlester A. Parker,7 Jennifer Bordeaux,7 Thomas Sicheritz-Ponten,1 Marina Olhovsky,4 Adrian Pasculescu,4 Jes Alexander,8 Stefan Knapp,9 Nikolaj Blom,1 Peer Bork,2,10 Shawn Li,6 Gianni Cesareni,5 Tony Pawson,4 Benjamin E. Turk,7 Michael B. Yaffe,8† Søren Brunak,1,2† Rune Linding4,8,11†

1 Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Lyngby, Denmark.2 The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.3 European Molecular Biology Laboratory, 69117 Heidelberg, Germany.4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.5 University of Rome, Tor Vergata, 00133 Rome, Italy.6 University of Western Ontario, London, Ontario, Canada N6A 5C1.7 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.8 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.9 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.10 Max-Delbrück-Centre for Molecular Medicine, 13092 Berlin, Germany.11 Cellular & Molecular Logic Team, The Institute of Cancer Research, London SW3 6JB, UK.* These authors contributed equally to this work.† To whom correspondence should be addressed. E-mail: [email protected] (S.B.), [email protected] (M.B.Y.), and [email protected] (R.L.)

A Sequence-Specificity Atlas of the Kinase World

© 2008 American Association for the Advancement of Science. All Rights Reserved.

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

ASGPKR

KR

SQHKR

YKNQRH T

SG

Pim2

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

LPTES

QSL

AGES

PS

DLS

TSQ

ESP

QS

SI

EDQS

VDSPLS

ATM/ATR

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

MGVLQS

VLHAGQFST

PSVG

TSQL

IEA

I

N

VGFDTP

TSQPLGAPEASLT

SLN

QQTGDVSAE

GEMNRVASPQT

GHKDFS

LEKQGPDS

TFSANPRGTLQ

DNAPK

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

ISTVAK

QNKPT

GELNPRTVKQS

LQSVGA

HLPQSYTKRA

LKR

NSTVILERK

TSLNGVS

YLANPSVCI

G

IKRDVSAG

SMI

GDRETVAK

KLRSWAITGEP

V

N

HF

AEPLG

PLGFA

AuroraB/AuroraC

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

LRTVPQK

KLPESAR

GKPSEQN

EKNQTLS

FKLQSTPR

GNQSCAVKLR

KRST

STGAKRV

GKTVLQP

IHSAEVP

FNVGKLP

NG

DQAK

NTKEPSLQEPAR

AuroraA

EIF2AK2

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

PMKI

ANLSD

IPQRKLMEV

GKNERTDPSL

MRKLPED

VTRMKI

GFALS

HEALPTK

GFDTVYELRS

TKNETVGLPR

YFEDARSTL

LNPDRYGKST

IMGVLESR

MGFRSDT

EPDRSTVGKL

LMGSTI

EDR

EphB3

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

EDNYA

DE

mTOR

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

FNDGPRST

GLNPRTVFQS

GKEMQTVI

PS

HLGRDTFEP

YVPKGFCLST

GTI

PSVR

HKFDQVNRTT

SFYP

IEPDRSGV

KTARSGD

KFPSTD

GI

EPVLRST

VKI

GFDALP

ILFDTVGPS

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

TDLRSE

RES

H

N

ESV

DTLSEV

INKLED

GQSLEDA

HP

T

IMEDLYS

AEVD

FEDNPQTYS

QSVGMLP

ELSTVNRP

MQEKNDP

NQE

LPEDGNRA

Tec family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

DSE

STLGPDE

MPDE

PSAED

NSED

ANSEDPSEVGDYT

MKAYLDVE

STNDE

EMALVPPD

PSE

PDE

Syk family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

ILPVASD

IGERTAHPSL

KGQEHSALP

K

EISLAT

HQI

DS

YTSFGALKD

GPEDYE

GKTPVI

AYL

PTVK

IMPETVLFENP

RKDVS

IKLTVHFEPD

KDRWATISP

EDSTG

JAK2/JAK3

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

ES

G

LKE

K

SDE

R

D

STEPGNDPEGDY I

AM

T

NS

VAP

IM

YNES

SGP

LPVKG

GK

InsR/IGF1R

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

SESEE

SDE

DESE

DTS

GSED

GSDE

TGSDE

GSDE

SDE

SDE

DE

CK2 family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

KS P

LS

L

P

PGST

SGHKLERPPASKV

LGSPKR

S KSLP

CDK1

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

S

LPS

ESS

SP

GTSHGTAP

ARGPS

QHPSTRK

PRLL

CDK2/CDK3

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

HKRTMNPS

IKPQSVLMR

YPKHADS

A

ILNAQPR

IHYP

MGFEALS

TSPY

TRIFLAP

IRSHTAP

ILHNFSVG

YTRNKI

HASV

KQETLAR

KLDPSTQRY

CDK4/CDK6

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

YSRP

IALG

ILPEVKHRS

YRKAESP

IGPQFSVNK

HI

MNQSKPR

GLFPQRTSVA

KGQFTYL

TS

KI

RTDHP

HKLFNPQSVYE

KLHGPTRV

KHNEAQSV

YSQPLKI

AT

MKHATRL

LMHGFSDVW

CDK7

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

R SSKRS

R TS

SKR

KGR

S

PKC family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

RTPSKR

TSKR

TS

PKA family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

KLS

DE

GPESL

RVNSTLE

LPG

DPLTSE

SDT

SKQSLPLEVS

ENPQRSDIL

TEVAPS

SA

KLDNAS

PLK1

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

KNVERGPLRAS

GFSTPL

GPSR

LNQTDAKSPRL

TVGAPQSEVPTL

TS

MRSVELP

FDNPRTES

GEPTVLDAS

IGEQTALPS

ELDRTVKPS

G

ES

GRTPA

MAPKAPK family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

ERV

SEDE

QSD

ETD

PRTES

PEVAGDT

SSTE

NGVDS

TLNQDGVS

GSEDQSG

GRK subfamily

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

LRA

NPQVDGTRSK

VAKPQE

ISR

YQPNEAKGDRS

VTQGASFYKR

KLEVHGSYR

IFTKLNPSYRS

TFLQRTGS

K

ST

QGVR

GTVRS

NI

AMS

LDAKGFRPSV

LS

KQYGEP

PSTGFDM

ROCK family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

LESTDAG

INGFQRSP

LRLGDRAPSRH

RLATS

GNPLVARSC

TS

Y

K

WNMLVA

RVASTPD

KQETDGLNS

QSVAT

IRVNS

ILKNEPSA

SEG

SGK family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

ILNFTVESD

HNGDYI

ES

MSLSTDGERN

FVANGED

RQKHDANSY

IKLFDTVSNEYF

EDSTAKIV

LFERDVYN

MPFRDVI

KL

HPTWALGRD

HKLQFSENP

STA

GFKPQRSE

FLT3/CSF1R/Kit

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

VI

KLRSTA

HGEQRTCDVS

SPMLKFEAGTD

YVNMKQEDS

IGDSVFLMT

LMAVTE

TQAPKDGM

SYT

ILMRDWGPV

METDVAY

DSWKTVA

SPNMDAGTRV

YSREAMCWT

KLGPVDYR

ILEDSWYPAR

MAP2K3/4/6/7

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

PDSI

EPS

STAPL

GSAPLT

SPLVAEPS

AP

EPAT

SS

JNK subfamily

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

PEPGV

PRTPES

GVSP

STALP

DVLSPT

SKEALSVGTRP

KRLSAPLSVGP

GLPQDVTSH

RSATP

PAS

SPA

GSK3 subfamily

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

MRYS

HPRSTGEDVA

SQMFEAL

IHD

TKEASVL

NPSEQRGD

IKPRSVADE

LMDCHSTNEYT

MLCYDVHKF

DVNSI

P

NELMPV

GHK

RYDTNP

YNLCQTAP

NTS

VRPLKASYGT

Met family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

S PS

SSGP

STALP

SLT

SAPG

SP

SPP

S

PSS

S

MAPK1/3/7/NLK

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

NRDLGEAS

SP

LNSAKEVG

KGEAFSD

VM

AKSLRT

RQMLKCGESATNQHTFSS

TNLPSYF

IHAETSVC

YSNMFEDPAG

IKLQVPST

YVNGDRSAITP

NI

ATDE

RQLHGDAFTSY

PDK1

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

PKRESTG

AGENPGEDS

GV YV

DAT

GTQ

KIVPPSVG

P

Abl family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

FGR

K

RSA

ISKAR

GSTLVKER

HQSTVGPAR

YVSHAGLKR

IL

ARVT

SI

KLQAR

GHEQTASL

GSNEP

RVEGAQ

APTKS

LPA

PKGcGK family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

RPGS

RS

YLGDASERLQEKRS

KSWAGPR

QALKRS

PKDMLGR

TSEDLSVR

NDGPES

GKNR

IPSPRSG

FEDSEDLFP

RSK family

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

HR ILM

R TS

RL

AMPK subfamily

CDK5

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

KTSPQ

RK

RHK

KHR

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

YWVFMIL

MR

HKR

AMSRQT

H

LNT

SWCMLFYI

HWCYRTS

CHK2

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

DE

TDESY

TDEYSF

YETDS

GDSAT

AGT

SCK1 family

LKB1

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

ASPYFW

MWYF

CTVL

IMRT C

WPT

DMPK family

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

LRLR

RLT

SLV

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

RCKPR

VQTSLRCP

KGASTYRT

SRGTSAP

PDRST

ICK

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

NPDE

PNDE

GSNDEP

TVID

EYTYVL

IF

IYF

WPMYILVF

VP

EGFR

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

CTYF

IVDLEYC

YQADE

NIYDVE

HFYL

IVP

EphA4

-7 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

RR H

KR S

R

CLK family

-6

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

YKR

KR

ST T

SMVL

IWF

NSGP

PKB family

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

WHKR

RQHKR

WQKNYRH T

SPim1

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

QTNHKR

RK

YSWKHR

KSHLYRT

YTS

HTNCSR

p70S6K subfamily

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

RR

SWHKR

VPSTHR

RTS

W

IFLY

PAK2

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

RNGWQSKR

HSYR

YKRT

SCFLSYMVI

W

VSYCALYFWS

PAK4

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

STNDRGYP

NQH

GWY

STQPHNGTC

WIML

CTSKR

WSTNHPKR

TSNKR

TNIK

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

KR

K

NQKHWR

WTFKHRY

KNYHRTR

IFYLWM

TGNHKR

HKR

NHKR

SLK

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

GSYW

MHTQAWY

YHMRKGNTCI

WLM

QNHRKPATSKRPKR

MST1

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

QR

R

NGCNRAHWY

YHMRNGTR

YTWCLVM

TGKR

KR

ATHGKR

MST4

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

SIVLP

GTMQT

SP F

MAPK14

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

TESD

GNTSDE

CTSHNEDT

SLRMNQ

DW W

TLK1/TLK2

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

AY

T

PAK

TMSIVL

TMSI

ALV

TSHRKEQK

RGHLMK

CWTS

YWIFLMV

IAVM

MWYF

MWYVF

YWPMF

PKD family

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

WFW

YGWMLF T

SLVTSMI

HTSR

NEK2

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

CKQNSTR

QKRNSDE

SNDEKRT

SMS

TGFbR2

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

GDE

GDEELTVI YND

EAQGE

WYFVIL

Lck

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

PEN

PEN

TS

YGTPSDE

TPSDE

TPSDE

TPSDEYL

EYMF

IVPEYD

YLMFIVE

PDGFR family

-7 -6 -5 -4 -3 -2 -1 0+

1+

2+

3+

4+

5+

6+

7

KRS

IKYARFL

QSELR

HGQVKPSTR

YMI

PASRQ

KREDAT

SI

H

T

KVFL

IKLREQSTDPREDS

EKSDLRI

GQSA

PSL

CaMKIIα/δ

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

RWYFK

KR

NMQ

KLFQMT

SYLMVIF

TE

ISD

TSLMI

K

WYKF

CaMKIIβ

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