Evolution of the Protein Kinase Family

Michael Gribskov

DEPARTMENT OF BIOLOGICAL SCIENCES

Protein - PProtein

ProteinKinase

Protein Phosphatase

Are Kinases PhosphoComputers?

• multiple sites = AND or OR calculators

P

P

P

PAND

OR

PX

PX

Kinase Roles

• Protein kinases play essential roles in eukaryotic cells

• Regulation of cell cycle, including structural elements• Regulation of enzymes• "signal transducer"

• response to environment• response to injury/disease/infection

• signal receiver

SignalingCascades

Protein Kinases

• Ser-Thr-Tyr Kinases are common to Eukaryotes (ePK)• Two component Systems (Histidine Kinases)

• Bacteria (HK >epK)• Archaea (HK >ePK)

• Fungi (ePK > HK)• Animals (ePK > HK)• Plants (ePK > HK)

Archael ePKs

Kennelly, P.J., (2003) Biochem. J. 379-389

Bacterial ePKs

• ePK?

• Pkn family• ABC1 family• RIO

Core Protein Kinases

• Ubiquitous• No extra domains• Paradigms: CK1, MAPK

• cell cycle• meiosis/mitosis• circadian cycle

MAPK Cascades in Yeast

Complex Kinases

• AGC family• CAMK family

• Second messenger regulated• Interact with regulatory subunits• Frequently become fused

Protein Kinase Superfamily

PKA

PKCPKGPKBcdk2

srcEGFR

Kinase Core

Catalytic SubunitRegulatory Subunit

DD cAMP cAMP

SH3 SH2

PH

C1 C2

EGF Binding Domain

DD cGMP cGMP

Kinase Roles

• Protein kinases play essential roles in eukaryotic cells

• Regulation of cell cycle, including structural elements• Regulation of enzymes• "signal transducer"

• response to environment• response to injury/disease/infection

• signal receiver

Some Receptor Kinases

(EGF receptor) (Insulin receptor) (FGF receptor)

Receptor Kinases

• Tyr-kinase in animals• Ser-Thr in plants• His in fungi and bacteria

• Clearly the last role to evolve

Receptor Tyrosine Kinase Activation

Complete Kinase Clustering

Yeast Signaling (MAPK)

Validating Transgenomic Predictions

SnRK

• At AKIN10 and AKin11• Rescue yeast SNF1 deletion• Functional homolog

GIN4/ERC47/CLA6/D9719.13/YDR507C KCC4/YCL024W HSL1/(SEL2)/NIK1/YKL453/YKL101W SNF1/CAT1/GLC2/CCR1/PAS14/HAF3/D8035.20/YDR477W

At5g39440 At3g29160/AKIN11 At3g01090/AKIN10 At5g58380 At5g07070 At5g01810 At5g45820 At4g30960 At5g25110 At5g10930 At2g25090 At2g30360 At5g01820/AtSR1 At2g38490 At3g23000/AtSR2 At4g14580 At1g01140 At1g30270 At2g26980 At4g24400 At5g35410/SOS2 At1g48260 At3g17510 At5g57630 At1g60940 At1g10940 At5g08590 At5g63650 At2g23030 At1g78290 At3g50500 At5g66880 At4g33950 At4g40010 At1g29230 At2g34180 At4g18700 At5g45810

KIN1/YD9727.17/YDR122W KIN2/L8004.3/L2546/YLR096W KIN4/KIN31/(KIN3)/O5220/YOR233W YPL141C/LPI5 YPL150W/P2597

50

E=10-80

See

Fig

. 2

 

Kinase Clustering and Classification

• Arabidopsis & Rice• Human• Drosophila• C. elegans• Yeast

CDC2

?

CDK7

PITSLRE

CRK7

PlantSpecific

Protein Kinase Family Size

• Yeast 130• C. elegans 454• D. melanogaster 239• H. sapiens 513

•A. thaliana 1000•O. sativa 1640•P. trichocarpa 2000+

Innate Immunity

Gene Duplications

Maize

Wheat

Rice

Brassica

Arabidopsis

Populus

CPK and PPCK

WAK14

4

6

25

31

Expanded families

Disease resistance

Self-incompatability

S locus RK

WAKL

WAK

Os Specific – lectin-like

SignalingCascades

Kinase Regulatory Systems

receptor

kinase cascade

Plant CIPK/CBL

MAPK Kinase Cascades

Caffrey et al (1999) J.Mol.Evol 49, 567-582.

Bioinformatics Group

• Gribskov Group• Staff• Emre Demiror• Hao Jiang• Ying Li

• Students• Omer Ahmad• Jin Tae Kwak• Kejie Li• Prasad Siddavatam• Reazur Rahman• Greg Ziegler

• San Diego Group• Fariba Fana• Degeng Wang• Sheila Podell• Jason Tchieu• Hannes Niedner

• Major Contributors• Douglas Smith• Jeff Harper• Catherine Chan• Alice Harmon• Estelle Hrabak• David Kerk• Shinhan Shiu

• Purdue Computational Genomics Facility

• Damion Junk• Doug Yatcilla

Aurora Kinases

Ste20 Family

Ste11 Family

3/3

Ste7 Family

MAPK

6/9

10/9

EssentialPhosphate

Maximal Linkage Clustering

Clustering

Clustering/Classification

• Pairwise distances• All-against-all BLAST

Uses entire sequence

Alignments not required

Longer matches, i.e. more domains, give better score

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-log( E-value )

Nu

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mb

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BLASTDistance

Entire Sequence

BLASTDistance

Non-KinaseDomain