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WNK Kinases, a Novel Protein Kinase Subfamily in Multi-Cellular Organisms

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WNK Kinases, a Novel Protein Kinase Subfamily in Multi-Cellular Organisms Oncogene (2001) 20, 5562 ± 5569 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc WNK kinases, a novel protein kinase subfamily in multi-cellular organisms Fa tima Verõ ssimo1 and Peter Jordan*,1 1Centre for Human Genetics, National Institute of Health `Dr. Ricardo Jorge', Lisbon, Portugal We have cloned and characterized a novel human serine/ movement, embryonic development and regeneration threonine protein kinase gene from chromosome 12p13.3 (Dhanasekaran, 1998). For instance, activation of both encoding 2382 amino acids. Remarkably, the catalytic growth factor receptors and integrin-mediated cell domain sequence contains a cysteine in place of a lysine adhesion are required to stimulate the mitogen- residue conserved in subdomain II of most kinases. The activated protein kinase (MAPK) cascades, organise same amino acid alteration was recently described for rat the cytoskeleton, and protect cells from apoptosis WNK1 (with no K=lysine) in which another nearby (Kumar, 1998). lysine residue was shown to confer kinase activity to the The MAP kinase cascades (reviewed by Denhardt, protein. Rat WNK1 is 85% identical to a splice variant 1996; Dhanasekaran and Reddy, 1998; Garrington and lacking exons 11 and 12 of the described human kinase Johnson, 1999; Chang and Karin, 2001) transduce which we have called human WNK1. The WNK1 extracellular signals from the plasma membrane to the catalytic domain has closest homology with human nucleus through activation of transcription factors that PAK2, MEKK3, and Raf-1. Three additional, partial elicit changes in gene expression and thus in cell human protein kinase sequences, WNK2, WNK3 and metabolism. The original MAPK pathway is activated WNK4, are also reported here with catalytic domains by growth factor receptors and involves the small that are 95% homologous to WNK1. These genes dier GTPase Ras. Activated Ras GTP binds to and both in chromosomal location and tissue-speci®c expres- activates the MAP kinase kinase kinase (MAP3K) sion. Moreover, we have identi®ed in the database a total Raf, thus initiating the Raf-MEK-ERK cascade. At of 18 WNK-related genes, all exclusively from multi- least three other kinase cascade pathways have now cellular organisms, which share a WNK kinase sequence been identi®ed involving the stress-activated protein signature within subdomains I and II of the catalytic kinases (SAPK/JNK), p38-MAPK and ERK5. These domain. We suggest that they constitute a novel pathways include activation of Rac or Cdc42 GTPases subfamily of protein kinases that evolved together with which activate MAP4Ks such as PAK which in turn cell adhesion and tissue-formation. Oncogene (2001) 20, stimulate speci®c MEKKs, MKKs and then JNK, p38 5562 ± 5569. MAPK or ERK5. More and more protein kinases have been described Keywords: protein kinase; catalytic domain; MAP in the last decades and from the sequence of the human kinases; chromosome 12; gene cloning; alternative genome a number of over 1000 is now estimated to splicing exist (Hunter, 2000), as was predicted almost 15 years ago (Hunter, 1987). This number re¯ects the current notion that signal transduction pathways are not linear Introduction cascades of events but rather complex networks and circuits of positive and negative feedback loops. Protein kinases form a superfamily of enzymes that act From the structural point of view protein kinases are as important mediators in the regulation of many an extremely heterogeneous family of proteins with cellular processes (Hunter, 2000). They become high homology over their catalytic domains. The activated by upstream signals and positively or catalytic domain is subdivided into 12 subdomains ONCOGENOMICS negatively regulate the activity of downstream protein comprising 250 ± 300 amino acids. Some of these substrates via phosphorylation. Protein kinases often residues are invariant and play a crucial role in provide `molecular switches' that rapidly and reversibly maintaining the two-lobed folding of the catalytic respond to speci®c signals and can integrate multiple domain, or in providing enzymatic activity (Hanks and signalling pathways in many dierent cellular responses Hunter, 1995). For example, subdomain I consists of such as cell growth, death, division, transformation, two b-strand structures that are separated by a loop containing invariant glycine residues. This glycine string acts like a ¯exible ¯ap covering and anchoring the non-transferable phosphate groups of ATP (Bosse- *Correspondence: P Jordan, Centro de Gene tica Humana, Instituto meyer, 1994). Another example is a conserved lysine Nacional de Sau de `Dr. Ricardo Jorge', Avenida Padre Cruz, 1649- residue in subdomain II of the catalytic core 016 Lisboa, Portugal; E-mail: [email protected] Received 23 March 2001; revised 14 June 2001; accepted 14 June (corresponding to Lys72 of protein kinase A) that 2001 anchors and orientates the a and b phosphoryl groups WNK1, a novel human protein kinase F VerõÂssimo and P Jordan 5563 of ATP (Knighton et al., 1991; Bossemeyer et al., 1993). In vitro mutagenesis of this residue, or the catalytic aspartate in subdomain VIb, have been used in many kinases to study the eect of kinase-dead mutants. Here we describe a novel protein kinase that has an unexpected amino acid sequence variation in subdom- ains I and II when compared to the conserved catalytic domain of other kinases. We report the ®rst human kinase among a number of related genes from various species and propose that they constitute a novel protein kinase subfamily. Figure 1 Analysis of the WNK1 coding sequence. (a) Schematic representation of the human WNK1 coding sequence. The protein Results kinase domain is shown in black, three potential coiled coil regions are shown in grey and four proline-rich regions (P) are patterned. (b) Sequence comparison of subdomains I and II in the Identification of a novel human protein kinase sequence catalytic domains of MAP kinases and the novel WNK1 gene. When the expression of protein kinases was studied by The distinct catalytically active lysine that acts in rat WNK1 Ser/ Thr-kinase (Xu et al., 2000) is marked and is conserved in human the Dierential Display technique (Liang et al., 1993) WNK1 in invasive colorectal cell lines a transcript for a novel serine/threonine kinase was identi®ed (unpublished data). Database comparison of this partial kinase contains three potential coiled-coil and four proline- clone revealed a related genomic kinase sequence from rich regions. A glutamine-rich region (residues 571 ± BAC clone RP11-388A16 on chromosome 12 (Gen- 812), two serine-rich regions (residues 1404 ± 1562, Bank accession number AC004765). In order to predict 2027 ± 2065) and a total of 33 PXXP motifs recognized the corresponding coding sequence the genomic raw by SH3 domains are present, as well as a potential data was analysed with the Genscan software which bipartite nuclear localization signal located between revealed many potential exons and extension of an residues 567 and 584 that overlaps the second coiled- open reading frame into the overlapping BAC clone coil region. RP11-359B12 (GenBank accession number AC004803). Human kinases with closest homology to the Gene prediction alone cannot currently identify exons catalytic domain of this novel protein are the serine/ in a reliable manner (see Jordan et al., 2000 and threonine-protein kinases STK2, PAK2, MEKK3, references therein). Typical prediction errors are that (i) PAK3 and Raf-1 (approximately 30% sequence intronic sequences are over-predicted as additional identity and 50% sequence homology). These homo- exons; (ii) small or alternatively spliced exons with logies suggest that the novel kinase is a member of the weaker splice site consensus values are missed; and (iii) mitogen-activated protein kinases. the exact position of one splice junction can be shifted A most remarkable feature of the novel kinase some nucleotides away, especially frequent in the ®rst sequence is the replacement of the conserved lysine coding exon. To overcome these problems the putative residue in subdomain II of the catalytic domain by a ®rst and last exon were checked for matching clones in cysteine (Figure 1b). This speci®c lysine residue is the EST-database and primers were designed to involved in ATP binding in almost all kinases amplify by RT ± PCR the coding sequence, as reported to date and has been frequently used to expressed in vivo. The corresponding cDNA product generate dominant negative protein kinase mutants. was then subcloned and sequenced. This approach Interestingly, a new rat protein kinase called WNK1 allowed us to determine the complete coding sequence (with no K (=lysine)) was recently shown to contain and to deduce the correct genomic structure of the the same lysine-to-cysteine alteration, and the authors gene. demonstrated that another nearby lysine residue, located within the glycine string of subdomain I, confers kinase activity (Xu et al., 2000; Figure 1b). Analysis of the WNK1 coding sequence The human kinase described here is 85.6% identical The complete coding sequence of the novel gene to rat WNK1 and thus corresponds to human encompasses 7149 bp or 2382 amino acids and codes WNK1. for a protein of 251 kDa (GenBank accession number During RT ± PCR ampli®cation of full-length AJ296290). Analysis of the coding sequence is shown WNK1 from human heart or colon cDNA, further in Figure 1a and reveals a protein kinase catalytic products were isolated that correspond to WNK1 domain between residues 221 and 479. The motifs splice variants lacking either exon 12, or exons 11 and `IIHRDLKCDNIFI' in subdomain VIb and `GTPEF- 12, or exons 9, 11 and 12. The ratio of expression of MAPE' in subdomain VIII further suggest that this the full length versus the alternatively spliced variants protein is a serine/threonine kinase (Taylor et al., remains to be determined. Interestingly, the recently 1995). In addition, the predicted amino acid sequence described rat WNK1 corresponds to the human splice Oncogene WNK1, a novel human protein kinase F VerõÂssimo and P Jordan 5564 variant lacking exons 11 and 12.
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