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Emerging Roles of Pseudokinases

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Emerging Roles of Pseudokinases Review TRENDS in Cell Biology Vol.16 No.9 Emerging roles of pseudokinases Je´ roˆ me Boudeau1, Diego Miranda-Saavedra2, Geoffrey J. Barton2 and Dario R. Alessi1 1 MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, UK, DD1 5EH 2 Division of Biological Chemistry and Molecular Microbiology, University of Dundee, Dundee, UK, DD1 5EH Kinases control virtually all aspects of biology. The location of these proteins on the phylogenetic tree of Forty-eight human proteins have a kinase-like domain kinases is illustrated in Figure 1 [1]. Pseudokinases are that lacks at least one of the conserved catalytic residues; scattered throughout the distinct protein kinase subfami- these proteins are therefore predicted to be inactive and lies, suggesting that they have evolved from diverse active have been termed pseudokinases. Here, we describe kinases. Twenty-eight pseudokinases have homologues in exciting work suggesting that pseudokinases, despite mouse, worms, flies and yeast that lack the equivalent lacking the ability to phosphorylate substrates, are still catalytic residues [1,2]. We have classified the human pivotal in regulating diverse cellular processes. We pseudokinases into seven groups (A to G) according to review evidence that the pseudokinase STRAD controls which of the three motifs in their pseudokinase domain the function of the tumour suppressor kinase LKB1 and they lack (Table 1). The amino acid sequence of each that a single amino acid substitution within the pseudo- pseudokinase and a description of missing conserved resi- kinase domain of the tyrosine kinase JAK2 leads to sev- dues are reported in the landmark study by Manning and eral malignant myeloproliferative disorders. We also colleagues [1]. discuss the emerging functions of other pseudokinases, Figure 2 shows a comparison of the domain structures of including HER3 (also called ErbB3), EphB6, CCK4 (also all human pseudokinases. Several, such as isoforms of called PTK7), KSR, Trb3, GCN2, TRRAP, ILK and CASK. STRAD, Trb, NRBP, SgK495, Slob, VRK3 and SuRTK106 (see Glossary), have a simple structure consisting essen- Introduction tially of only a pseudokinase domain. Others, such as Protein kinases regulate the function of a large fraction of isoforms of ANP, CASK, CCK4 (also called PTK7), EphB6, cellular proteins by catalyzing the covalent attachment of EphA10 and TRRAP, are part of much larger multi-domain phosphate onto Ser, Thr and Tyr residues in target pro- proteins and are likely to have functions independent of teins. In recent years, genome-wide analyses have led to their pseudokinase domain (Figure 2). Intriguingly, the the complete description of the protein kinase complement four Janus tyrosine kinases (JAK1, JAK2, JAK3 and Tyk2) of several eukaryotic organisms, including human [1], and the serine/threonine kinase GCN2 have a pseudoki- mouse [2], Caenorhabditis elegans [3], Dictyostelium [4] nase domain and a functional kinase domain within the and yeast [5,6]. These studies have revealed that 2–3% of same polypeptide; the implications of this particular struc- all eukaryotic genes encode proteins containing a kinase ture are discussed in more detail below. domain. Unexpectedly, 10% of these proteins lack one or Not all kinase domains that lack essential catalytic more of the conserved amino acids in the kinase domain residues are inactive. For example, the four isoforms of that are required for catalytic activity; they are therefore the kinase WNK were originally classified as ’unusual’ as predicted to be catalytically inactive. Sequence analysis of they lacked the invariant catalytic lysine residue in the these ‘pseudokinases’ indicates that they lack at least one VAIK motif in subdomain II of the catalytic domain [7]. of three motifs in the catalytic domain that are essential for However, WNK1 is catalytically active and structural catalysis. The three motifs are: the Val-Ala-Ile-Lys (VAIK) analysis of its catalytic domain demonstrates that a lysine motif in subdomain II of the kinase domain, in which the residue in subdomain I substitutes for the missing lysine lysine residue interacts with the a and b phosphates of residue in subdomain II [8]. Similarly, the kinase PRPK, ATP, anchoring and orienting the ATP; the His-Arg-Asp despite lacking the lysine residue equivalent to that miss- (HRD) motif in subdomain VIb, in which the aspartic acid ing in the WNK isoforms, is catalytically active [9].Itis is the catalytic residue, functioning as a base acceptor to possible that a lysine residue in a AVIK motif that is achieve proton transfer; and the Asp-Phe-Gly (DFG) motif conserved in all eukaryotic and archaeal PRPK homolo- in subdomain VII, in which the aspartic acid binds the gues (Lys60 in human PRPK) substitutes for the canonical 2+ Mg ions that coordinate the b and g phosphates of ATP in lysine residue (G. Manning, personal communication). the ATP-binding cleft. Haspin was originally reported to lack the conserved magnesium-binding DFG motif in subdomain VII of the An inventory of human pseudokinases catalytic domain, but recently another motif, Asp-Tyr-Thr- Out of 518 protein kinases encoded by the human genome Leu-Ser (DYTLS), has been suggested to substitute for this (the ‘kinome’), 48 have been classified as pseudokinases [1]. key motif [10] and there is biochemical evidence that haspin might function as an active kinase [11,12]. There Corresponding author: Alessi, D.R. ([email protected]). has also been some debate as to whether titin (TTN), a Available online 1 August 2006. protein that has over 26 000 residues, is catalytically www.sciencedirect.com 0962-8924/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2006.07.003 444 Review TRENDS in Cell Biology Vol.16 No.9 Glossary Pseudokinase abbreviations TTN: giant muscle filament protein titin ULK: UNC (uncoordinated)-51-like kinase ANP: atrionatriuretic peptide receptor (guanylate cyclase) VACAMKL: vesicle-associated CaM kinase-like CAK1: Cyclin-dependent kinase-activating kinase 1 VRK: vaccinia-related kinase CASK: calcium/calmodulin-dependent serine kinase CCK4: colon carcinoma kinase 4 Other abbreviations CYGF: guanylate cyclase 2D (GUCY2D) ATF: activating transcription factor CYGF: guanylate cyclase 2F (GUCY2F) ATM: ataxia-telangiectasia mutated kinase Drl: derailed CDC: cell division cycle Eph: erythropoietin-producing hepatocyte (Eph); ephrin receptor CHOP: C/EBP homologous protein ErbB: v-erb-b2 erythroblastic leukemia viral oncogene homolog COP1: constitutive photomorphogenic protein-1 GCN2: general control non-derepressible 2 DNA-PK: DNA-dependent protein kinase HER: human epidermal growth factor receptor EGFR: epidermal growth factor receptor HSER: heat stable enterotoxin receptor (GUCY2C; guanylate cyclase 2C) ERK: extracellular signal-regulated kinase ILK: integrin-linked kinase FERM: band F ezrin-radixin-moesin homology domains IRAK: interleukin-1 receptor-associated kinase HEAT: Huntington, elongation factor 3, PR65/A, TOR domain JAK: Janus kinase IFN-g: interferon-g JH: JAK homology domains IL: interleukin JNK: c-Jun N-terminal kinase LIM: Lin-11, Isl-1, Mec-3 homology domains KSR: kinase suppressor of Ras MAPK: mitogen-activated protein kinase MLKL: mixed lineage kinase-like MEK: MAPK/ERK kinase NRBP: nuclear receptor binding protein MO25: mouse protein 25 OTK: off-track kinase mTOR: mammalian target of rapamycin PIKK: phosphatidylinositol 3-kinase-related kinase PDZ: PSD-95 (post-synaptic density protein 95), discs large protein, ZO-1 (zonula PRPK: p53-related protein kinase occludens protein 1) homology domains PSKH: protein serine kinase H PI3-K: phosphatidylinositol 3-kinase PTK7: protein tyrosine kinase 7 PKC: protein kinase C RSKL: ribosomal protein S6 kinase-like PTB: phosphotyrosine binding domain Ryk: receptor-like tyrosine kinase RTK: receptor protein-tyrosine kinase SgK: sugen kinase SAM: sterile alpha motif STRAD: STE20-related adaptor protein SH: Src homology SuRTK106: serine threonine tyrosine kinase 1 (STYK1) STAT: signal transducers and activators of transcription TBCK: tubulin-binding cofactor kinase WNK: with-no-K(Lys) kinase TRRAP: transactivation-transformation domain-associated protein ZAP-70: zeta-chain-associated protein kinase-70 Trb: Tribbles homolog active. All vertebrate homologues of titin contain a that it lacks other residues that are required for kinase glutamic acid residue instead of an aspartic acid at the activity [2]. Attempts to convert human HER3 to an active DFG motif in subdomain VII, whereas this residue is an kinase by reinstating the HRD motif and other potentially aspartic acid in invertebrate titin-like kinases. The 3D lacking residues have failed to restore activity [17]. structure of the catalytic domain of titin reveals that it It is possible that some of the 48 pseudokinases listed in is an active kinase that is maintained in an auto-inhibited Figures 1 and 2, many of which have not been studied, conformation and is activated by phosphorylation of a might turn out to have catalytic activity when analyzed. tyrosine residue in the kinase domain and through Caution should be taken when expressing a pseudokinase interaction with Ca2+ and calmodulin [13,14]. in mammalian cells and assessing whether it has catalytic Similarly, there is uncertainty about whether the Wnt activity. As discussed below, several pseudokinases form receptor tyrosine kinase Ryk, which regulates axon gui- complexes with active protein kinases that might be dance, is a pseudokinase. Mammalian
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