The protein kinases of Caenorhabditis elegans : A model for signal transduction in multicellular organisms

Abstract

Caenorhabditis elegans should soon be the first multicellular organism whose complete genomic sequence has been determined. This achievement provides a unique opportunity for a comprehensive assessment of the signal transduction molecules required for the existence of a multicellular animal. Although the worm C. elegans may not much resemble humans, the molecules that regulate signal transduction in these two organisms prove to be quite similar. We focus here on the content and diversity of protein kinases present in worms, together with an assessment of other classes of proteins that regulate protein phosphorylation. By systematic analysis of the 19,099 predicted C. elegans proteins, and thorough analysis of the finished and unfinished genomic sequences, we have identified 411 full length protein kinases and 21 partial kinase fragments. We also describe 82 additional proteins that are predicted to be structurally similar to conventional protein kinases even though they share minimal primary sequence identity. Finally, the richness of phosphorylation-dependent signaling pathways in worms is further supported with the identification of 185 protein phosphatases and 128 phosphoprotein-binding domains (SH2, PTB, STYX, SBF, 14-3-3, FHA, and WW) in the worm genome. R eversible protein phosphorylation plays a central role in regulating basic functions of all eukaryotes such as DNA replication, cell cycle control, gene transcription, protein translation, and energy metabolism. Protein phosphorylation is also required for more advanced functions in higher eukaryotes such as cell, organ, and limb differentiation, cell survival, synaptic transmission, cell-substratum and cell-cell communication, and to mediate complex interactions with the external environment. Because aberrant protein phosphorylation is commonly the cause of cancer and other human diseases, a comprehensive knowledge of the key enzymes that regulate these functions can provide the basis for novel therapeutic intervention strategies.The genomic revolution promises to provide a new paradigm for drug discovery, allowing one to selectively target the molecular basis of human disease. The completion of the Caenorhabditis elegans genome sequence gives us an opportunity to decipher the molecular nature of its signal transduction machinery. Several global analyses of proteins and protein domains present in C. elegans have been presented elsewhere (1-4), revealing that protein kinases comprise the second largest family of protein domains in worms. The three most frequently occurring protein domains found in worms are seven transmembrane chemoreceptors (650 domains, 3.5% of genome), protein kinases (496 domains, 2.6% of genome), and zinc finger C4 domains, including nuclear hormone receptors (275 domains, 1.4% of genome). A more in-depth analysis has been performed on the 535 worm proteins containing zinc-binding domains, including the C4, C2H2, and C3HC4 ring finger types (3), and on the 83 worm homeobox transcription factors (4). Here, we present a comparative ana...

Caenorhabditis elegans mom-4 is required for the activation of the p38 MAPK signaling pathway in the response to Pseudomonas aeruginosa infection

“…Previous studies demonstrated that TAK1 plays important roles in immunological and developmental contexts across many species (Plowman et al, 1999;Sakaguchi et al, 2004;Wan et al, 2006;Delaney et al, 2006;Kajino et al, 2008). In mammalian tissues, TAK1 is essential for responses to a variety of inflammatory ligands, it can involve in p38 activation by MKK3/6 or in JNK activation by MKK4/7 (Kim et al, 2005).…”

Comparative Analysis of the Receptor-Like Kinase Family in Arabidopsis and Rice[W]

“…The RLK/Pelle family is defined as the clade that contains RLK/Pelle representative sequences and forms sister group relationships to Raf kinases and receptor tyrosine kinases. The other kinase families were defined based on the kinase classification schemes for budding yeast (Hunter and Plowman, 1997), worm (Plowman et al, 1999), and human kinases (Manning et al, 2002). Two to three representative sequences from each kinase family in each organism were chosen to generate alignments with Arabidopsis or rice kinases.…”

The Arabidopsis CDPK-SnRK Superfamily of Protein Kinases

“…The Arabidopsis genome encodes 1,085 typical protein kinases (M. Gribskov, unpublished data), which is about 4% of the predicted 25,500 genes (Arabidopsis Genome Initiative, 2000). Not only is the proportion of Arabidopsis kinase genes about twice that found in Brewer's yeast (Saccharomyces cerevisiae; Hunter and Plowman, 1997) or Caenorhabditis elegans (Plowman et al, 1999), but there are also major differences in the types of kinases found in plants. For example, receptor kinases in plants phosphorylate Ser and Thr residues, whereas in animals, the predominant type of receptor kinase phosphorylates Tyr residues.…”