Chapter 15 : Protein Kinases Regulating Proliferation and Development

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This chapter briefly considers the major features of cell cycle control to provide a general context for the discussion of cell proliferation regulators. Progression through the cell cycle phases is controlled by the cyclin-dependent protein kinases (CDKs). These enzymes phosphorylate a number of substrates involved in processes such as in initiation of DNA synthesis or chromosome segregation. The molecular machinery controlling cell cycle progression is in essence a mere effector of signaling pathways, which are activated by a variety of intra- or extracellular stimuli. The life cycle of malaria parasites is an alternation of developmental stages where the parasite is cell cycle arrested, and stages undergoing intense cell division. The alternation of actively dividing and cell cycle- arrested developmental stages during the life cycle of malaria parasites must be associated with an efficient and versatile cell cycle control machinery, whose activity needs to be integrated with specific cell development programs. The underlying principles of cell division control at the molecular level and the identity of key players in this process such as CDKs, cyclins, and CDK inhibitors (CKIs) have been elucidated mostly through genetic analysis in yeast. The genome encodes a number of proteins putatively involved in calcium signaling, including calmodulin-related proteins, a calcium-transporting ATPase, and a family of CDPKs, which are composed of a protein kinase catalytic domain fused to a calcium-binding domain.

Citation: Doerig C. 2005. Protein Kinases Regulating Proliferation and Development, p 290-310. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch15

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RNA Polymerase II
Origin Recognition Complex
Malaria Life Cycle
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Image of FIGURE 1

Plasmodial protein kinases clustering within the CMGC family. The figure depicts only the CMGC branch of a larger tree constructed (by J. Packer, Abbott Laboratories) from a Hidden Markov Model-derived alignment of all protein kinases in the genome. Four human protein kinases (underlined) representing the four major families in the CMGC group (CDKs, MAPKs, GSK3, and CDK-like) were included in the alignment to anchor the position of these families in the tree. Branches with bootstrap values >40 are shown with dashes. The scale bar represents 0.1 mutational changes per residue (10 PAM units). Although some plasmodial sequences clearly cluster with established families (e.g., PfPK5 with CDK1/2 or Pfmap-1 and Pfmap-2 with the MAPKs), others (e.g., those labeled “CMGC-like” on the figure, because their branch originates near the base of the branch containing the CDK, MAPK and GSK3 groups) are much more difficult to classify. Adapted from Ward et al., 2004, which should be consulted for details, including bootstrap values.

Citation: Doerig C. 2005. Protein Kinases Regulating Proliferation and Development, p 290-310. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch15
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Image of FIGURE 2

Raw microarray expression data for the CDK-related protein kinases and cylins compiled from the files from the Bozdech et al. study and made available on PlasmoDB (www.plasmodb.org). See Bozdech et al., 2003, and the PlasmoDB website for details.

Citation: Doerig C. 2005. Protein Kinases Regulating Proliferation and Development, p 290-310. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch15
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Image of FIGURE 3

Plasmodial CDK-related kinases and cyclins, with potential upstream regulators and substrates. The figure shows selected elements, with their PlasmoDB identifier, of each pathway known to operate in . The lists given in each box do not pretend to be exhaustive, as only a subset of relevant elements was included. Furthermore, extensive cross talk most likely operates between pathways, but no attempt was made at illustrating this. Likewise, for the sake of clarity and concision, only a small number of potential substrate groups are shown.Asterisks in the central box indicate those elements for which putative homologs in other systems are involved in transcriptional regulation in addition to or instead of direct cell cycle control.

Citation: Doerig C. 2005. Protein Kinases Regulating Proliferation and Development, p 290-310. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch15
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Generic image for table

The plasmodial CMGC (CDK, MAPK, GSK3 and CDK-like) protein kinases and associatedproteins

Citation: Doerig C. 2005. Protein Kinases Regulating Proliferation and Development, p 290-310. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch15

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