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Cell regulation
Cell regulation Editorial overview Claude Prigent and Bruno Goud Current Opinion in Cell Biology 2006, 18:127–129
0955-0674/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2006.02.014
Claude Prigent CNRS UMR6061 Universite´ de Rennes 1, Ge´ne´tique et De´veloppement, IFR140, 2 Av Pr Leon Bernard, CS 34317, 35043 Rennes cedex, France
Claude Prigent is the director of the CNRS Unit UMR6061 ‘‘Genetics and Development’’ and the head of the ‘‘Mitotic protein kinases and oncogenesis’’ research group within the Polarity, Cell Cycle and Signalling Department. His laboratory aims to search for human protein kinases that control mitotis, to analyse their functions by identifying their substrates and to understand how they can be at the origin of cancer. Bruno Goud CNRS UMR 144 Institut Curie, Compartimentation et Dynamique Cellulaires, Institut Curie, 26 rue d’Ulm 75248 Paris cedex 05, France
Bruno Goud is the director of the CNRS Unit UMR144 ‘‘Subcellular Structure and Cellular Dynamic’’ (Department of Cell Biology) and the head of the ‘‘Molecular mechanisms of intracellular transport’’ research group. His research work is focused on the study of the regulation of vesicular transport and membrane traffic in eukaryotic cells.
If we were to give a summary of our current knowledge in cell signalling and a prediction of what to expect in this field for the future, it would undoubtedly be: complexity and more complexity. Using classical approaches such as genetic screens, it has been possible to uncover major signalling pathways that gave us the basis of cell regulation, mainly in model organisms like yeasts. These recent years have seen the arrival of a vast amount of information obtained with the complete genome sequences of various species, including vertebrates such as human. First of all, simple database searches with the sequences of proteins involved in ‘old’ existing cell signalling pathways have revealed families of proteins, sometimes present only in multicellular organisms, like the poly(ADP)ribose polymerases (See Gagne´ et al.), or more often present only in vertebrates, like some MCM proteins (See Maiorano et al.). Genome sequence information helped by bioinformatics evolution has also boosted proteomic approaches by allowing easier protein identifications. Expected cross-talks between existing pathways have been proved and, more importantly, unexpected relationships between signaling pathways have been uncovered. But given the complexity and quantity of the information available, we must give particular attention to bioinformatics approaches, such has gene-ontology, that have revealed new protein–protein interactions and consequently new networks. 2005 has seen a few breakthroughs reported here: one could single out the identification of auxin receptor (see Parry and Estelle) and PAR6 signaling pathway (see Bose and Wrana). The issue starts with the master molecule: the DNA that carries the genetic information of the cell, that needs to be replicated at every cell cycle and that is eventually equally inherited by each daughter cell after mitosis. The first challenge of the cell is to duplicate its genome; then the cell has to decide where to start and consequently where to assemble replication initiation complexes. MCM proteins form a family of conserved proteins that form a complex involved in the initiation of eukaryote DNA replication. While the structure of the DNA molecule that has to be replicated has remained unchanged, the number of MCM proteins has increased with evolution. The reason for this diversity is not known. Although ATPase and helicase activities are associated to MCM proteins, the function of some of them remains to be found. Maiorano, Lutzmann and Me´chali update our knowledge on this family of proteins used as markers for cancer prediction. Everybody knows that nude DNA does not exist in the cell; the molecule is wrapped around histones and organized in nucleosome structures that protect multiple functions during the life of the cell.
www.sciencedirect.com
Current Opinion in Cell Biology 2006, 18:127–129
128 Cell regulation
Post-translational modifications of histones, such as phosphorylation, acetylation, methylation, etc, are known to play important roles in the control of transcription. In the past few years their involvement in DNA repair has taken the lead. The review by Wurtele and Verreault presents an update of histone modifications that modulate DNA double-strand break repair. To continue with DNA repair, poly(ADP-ribose), which shows 500-fold increase upon DNA damage, is a posttranslational modification catalysed by an ‘old’ enzyme discovered in the 1960s. To confirm the complexity of cellular processes in multicellular organisms, one must realise that poly(ADP-ribose) does not exist in yeast while to date mammalian cells possess 18 different potential poly(ADP-ribose) polymerases (some without proven catalytic activity, however) and only one gene encoding poly(ADP-ribose) glycosylase, an enzyme that removes the poly(ADP-ribose). As reported by Gagne´, Hendzel, Droit and Poirier, the function of the modification, including the length of the chain, is largely unknown. The paper that follows indirectly deals with another important modification: the ubiquitinylation that in this particular case triggers protein degradation to control gene expression. Indeed this past year saw the mode of action of the hormone auxin elucidated in two very nice papers. The hormone turns out to directly bind to the Fbox protein TIR1, thus identified as the auxin receptor. The binding induces the degradation of transcription repressors leading to gene expression. The review by Parry and Estelle tells us the auxin story. Then with the next paper we move from extracellular to intracellular signals. Peter Cullen explains how Ca2+ signal can modulate Ras signalling. The role of Ca2+ in various cellular mechanisms has been known for quite a long time, but understanding how local increases in Ca2+ concentration (microdomains) and how the amplitude and frequency of the Ca2+ signal (oscillation) control Ras signalling remains a challenge. The review focuses here on how cells decode the spatial and temporal dynamics of Ca2+ signals through the GTPase Ras from the plasma membrane to the endomembranes. It was recently found that enzymes modifying Ras were localised on the Golgi and the endoplasmic reticulum, suggesting that Ras could signal through cellular membrane trafficking. Nice experiments using GFP-Ras have indeed shown that Ras localises to the Golgi prior to traffic to the plasma membrane through endomembranes. However, a retrograde traffic from the PM to the Golgi has also been observed. These observations clearly raise the question of Ras activation. To aid progress on this topic, Quatela and Philips present an update on this compartmentalised signalling of Ras, particularly on the Golgi. Current Opinion in Cell Biology 2006, 18:127–129
To remain at the Golgi level, it is now well established that actin and actin-binding proteins play an important role in the maintenance of Golgi structure. Their involvement in the formation and transport of vesicles that go out from the Golgi is still a matter of debate. Egea, La´zaro-Die´guez and Vilella and co-workers present the literature in favour of a role for the actin cytoskeleton in the biogenesis of Golgi-derived transport carriers. They also underline the peculiarity of the Golgi actin cytoskeleton in neuronal cells. From actin to microtubules! Nogales and Wang give an overview of our knowledge on microtubule dynamics. How does it grow? How does it shrink? The classical view of a microtubule as a cylinder made of 13 protofilaments shown in most textbooks has evolved. There is now evidence that a microtubule is not only a tube that varies in length: several structural intermediates exist in the cell. For instance, protofilaments first polymerise, then associate to form a sheet that eventually closes to form the tube. These intermediates show curvature that depends on the tubulin monomers’ conformation imposed by their nucleotide state, which also regulates the stability. During cell cycle progression the most dynamic microtubules are found in the mitotic spindle that forms after the activation of the cyclinB/Cdk1 protein kinase. A CDC25 phosphatase is directly responsible for this activation, cyclin/Cdk being its only substrates. Mammalian cells possess three CDC25 phosphatases (A, B and C). Boutros, Dozier and Ducommun explain us how these different isoforms of CDC25 cooperate to regulate cell cycle division and response to DNA damage and why CDC25 is a good target to develop drugs for cancer treatment. While CDC25 dephosphorylates CDKs and activates Cyclin/CDKs complexes, there is an emerging family of proteins that, like cyclin, can directly bind to the cyclin-dependent kinase and activate it. Angel Nebreda provides an up-to-date review on these proteins, focusing on the Ringo/speedy family of CDK1/CDK2 activators, which have been found only in vertebrates. Ringo and speedy were originally isolated from Xenopus, where they can induce a rapid meiotic maturation by activating CDKs. The functions of human Ringo/Speedy proteins during the somatic cell cycle are discussed. To keep going with cell cycle progression and in particular with mitosis, Narumiya and Yasuda present the literature indicating that Rho GTPases, especially Cdc42, are not only involved in cytokinesis but also in spindle assembly and chromosome alignment and attachment during mitosis. The authors discuss experimental evidence for and against a role of Cdc42 in mitosis; this remains controversial even though upstream regulators www.sciencedirect.com
Editorial overview Prigent and Goud 129
and downstream effectors of Rho GTPases have been found to be involved in various stages of mitosis. While the previous reviews have described internal cellular signalling pathways, the three next papers focus on cell-to-cell signalling. Partitioning-defective 6 (PAR6) is an adaptor protein involved in cell polarity and in controlling epithelial polarity, polarized cell migration and asymmetric cell division. Together with Cdc42, whose function in mitosis was described in the previous paper, it forms multiprotein complexes. Here Bose and Wrana report how PAR6 is regulated by extracellular signals, particularly focusing on the TGFb pathway and how TGFb-dependent phosphorylation of PAR6 triggers the tight junction loss involved in epithelial-to-mesenchymal transition, which is correlated with cancer progression. The following paper by Roland Le Borgne covers the most recent advances on the endocytosis and endosomal trafficking of Notch and its ligands. Notch signalling has an evolutionarily conserved role in mediating cell–cell
www.sciencedirect.com
interactions in many different cellular contexts during development. A number of studies have shown that intracellular trafficking of the Notch receptor and its ligands are intimately connected to Notch activation. Finally, the last paper of this issue is dedicated to neurotransmission. Organization of synaptic vesicles that will be released upon depolymerisation to ensure communication between neurones is the main topic of this review. Olsen, Moore, Nicoll and Bredt provide an update on the relation between MALS/Veli family of protein and the network of interacting proteins that defines their interaction with Liprins. These proteins participate to a synaptic network that ensures efficient neurotransmission. So this issue dedicated to complexity issue finishes with a paper related to the most complex area in biology: the brain. We would like to apologize for signalling areas not covered in this issue, and for the authors whose work could not be included for reasons of space. We have tried to give a taste of major advances in cell signalling that went out this past year.
Current Opinion in Cell Biology 2006, 18:127–129
0955-0674/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2006.02.014
Claude Prigent CNRS UMR6061 Universite´ de Rennes 1, Ge´ne´tique et De´veloppement, IFR140, 2 Av Pr Leon Bernard, CS 34317, 35043 Rennes cedex, France
Claude Prigent is the director of the CNRS Unit UMR6061 ‘‘Genetics and Development’’ and the head of the ‘‘Mitotic protein kinases and oncogenesis’’ research group within the Polarity, Cell Cycle and Signalling Department. His laboratory aims to search for human protein kinases that control mitotis, to analyse their functions by identifying their substrates and to understand how they can be at the origin of cancer. Bruno Goud CNRS UMR 144 Institut Curie, Compartimentation et Dynamique Cellulaires, Institut Curie, 26 rue d’Ulm 75248 Paris cedex 05, France
Bruno Goud is the director of the CNRS Unit UMR144 ‘‘Subcellular Structure and Cellular Dynamic’’ (Department of Cell Biology) and the head of the ‘‘Molecular mechanisms of intracellular transport’’ research group. His research work is focused on the study of the regulation of vesicular transport and membrane traffic in eukaryotic cells.
If we were to give a summary of our current knowledge in cell signalling and a prediction of what to expect in this field for the future, it would undoubtedly be: complexity and more complexity. Using classical approaches such as genetic screens, it has been possible to uncover major signalling pathways that gave us the basis of cell regulation, mainly in model organisms like yeasts. These recent years have seen the arrival of a vast amount of information obtained with the complete genome sequences of various species, including vertebrates such as human. First of all, simple database searches with the sequences of proteins involved in ‘old’ existing cell signalling pathways have revealed families of proteins, sometimes present only in multicellular organisms, like the poly(ADP)ribose polymerases (See Gagne´ et al.), or more often present only in vertebrates, like some MCM proteins (See Maiorano et al.). Genome sequence information helped by bioinformatics evolution has also boosted proteomic approaches by allowing easier protein identifications. Expected cross-talks between existing pathways have been proved and, more importantly, unexpected relationships between signaling pathways have been uncovered. But given the complexity and quantity of the information available, we must give particular attention to bioinformatics approaches, such has gene-ontology, that have revealed new protein–protein interactions and consequently new networks. 2005 has seen a few breakthroughs reported here: one could single out the identification of auxin receptor (see Parry and Estelle) and PAR6 signaling pathway (see Bose and Wrana). The issue starts with the master molecule: the DNA that carries the genetic information of the cell, that needs to be replicated at every cell cycle and that is eventually equally inherited by each daughter cell after mitosis. The first challenge of the cell is to duplicate its genome; then the cell has to decide where to start and consequently where to assemble replication initiation complexes. MCM proteins form a family of conserved proteins that form a complex involved in the initiation of eukaryote DNA replication. While the structure of the DNA molecule that has to be replicated has remained unchanged, the number of MCM proteins has increased with evolution. The reason for this diversity is not known. Although ATPase and helicase activities are associated to MCM proteins, the function of some of them remains to be found. Maiorano, Lutzmann and Me´chali update our knowledge on this family of proteins used as markers for cancer prediction. Everybody knows that nude DNA does not exist in the cell; the molecule is wrapped around histones and organized in nucleosome structures that protect multiple functions during the life of the cell.
www.sciencedirect.com
Current Opinion in Cell Biology 2006, 18:127–129
128 Cell regulation
Post-translational modifications of histones, such as phosphorylation, acetylation, methylation, etc, are known to play important roles in the control of transcription. In the past few years their involvement in DNA repair has taken the lead. The review by Wurtele and Verreault presents an update of histone modifications that modulate DNA double-strand break repair. To continue with DNA repair, poly(ADP-ribose), which shows 500-fold increase upon DNA damage, is a posttranslational modification catalysed by an ‘old’ enzyme discovered in the 1960s. To confirm the complexity of cellular processes in multicellular organisms, one must realise that poly(ADP-ribose) does not exist in yeast while to date mammalian cells possess 18 different potential poly(ADP-ribose) polymerases (some without proven catalytic activity, however) and only one gene encoding poly(ADP-ribose) glycosylase, an enzyme that removes the poly(ADP-ribose). As reported by Gagne´, Hendzel, Droit and Poirier, the function of the modification, including the length of the chain, is largely unknown. The paper that follows indirectly deals with another important modification: the ubiquitinylation that in this particular case triggers protein degradation to control gene expression. Indeed this past year saw the mode of action of the hormone auxin elucidated in two very nice papers. The hormone turns out to directly bind to the Fbox protein TIR1, thus identified as the auxin receptor. The binding induces the degradation of transcription repressors leading to gene expression. The review by Parry and Estelle tells us the auxin story. Then with the next paper we move from extracellular to intracellular signals. Peter Cullen explains how Ca2+ signal can modulate Ras signalling. The role of Ca2+ in various cellular mechanisms has been known for quite a long time, but understanding how local increases in Ca2+ concentration (microdomains) and how the amplitude and frequency of the Ca2+ signal (oscillation) control Ras signalling remains a challenge. The review focuses here on how cells decode the spatial and temporal dynamics of Ca2+ signals through the GTPase Ras from the plasma membrane to the endomembranes. It was recently found that enzymes modifying Ras were localised on the Golgi and the endoplasmic reticulum, suggesting that Ras could signal through cellular membrane trafficking. Nice experiments using GFP-Ras have indeed shown that Ras localises to the Golgi prior to traffic to the plasma membrane through endomembranes. However, a retrograde traffic from the PM to the Golgi has also been observed. These observations clearly raise the question of Ras activation. To aid progress on this topic, Quatela and Philips present an update on this compartmentalised signalling of Ras, particularly on the Golgi. Current Opinion in Cell Biology 2006, 18:127–129
To remain at the Golgi level, it is now well established that actin and actin-binding proteins play an important role in the maintenance of Golgi structure. Their involvement in the formation and transport of vesicles that go out from the Golgi is still a matter of debate. Egea, La´zaro-Die´guez and Vilella and co-workers present the literature in favour of a role for the actin cytoskeleton in the biogenesis of Golgi-derived transport carriers. They also underline the peculiarity of the Golgi actin cytoskeleton in neuronal cells. From actin to microtubules! Nogales and Wang give an overview of our knowledge on microtubule dynamics. How does it grow? How does it shrink? The classical view of a microtubule as a cylinder made of 13 protofilaments shown in most textbooks has evolved. There is now evidence that a microtubule is not only a tube that varies in length: several structural intermediates exist in the cell. For instance, protofilaments first polymerise, then associate to form a sheet that eventually closes to form the tube. These intermediates show curvature that depends on the tubulin monomers’ conformation imposed by their nucleotide state, which also regulates the stability. During cell cycle progression the most dynamic microtubules are found in the mitotic spindle that forms after the activation of the cyclinB/Cdk1 protein kinase. A CDC25 phosphatase is directly responsible for this activation, cyclin/Cdk being its only substrates. Mammalian cells possess three CDC25 phosphatases (A, B and C). Boutros, Dozier and Ducommun explain us how these different isoforms of CDC25 cooperate to regulate cell cycle division and response to DNA damage and why CDC25 is a good target to develop drugs for cancer treatment. While CDC25 dephosphorylates CDKs and activates Cyclin/CDKs complexes, there is an emerging family of proteins that, like cyclin, can directly bind to the cyclin-dependent kinase and activate it. Angel Nebreda provides an up-to-date review on these proteins, focusing on the Ringo/speedy family of CDK1/CDK2 activators, which have been found only in vertebrates. Ringo and speedy were originally isolated from Xenopus, where they can induce a rapid meiotic maturation by activating CDKs. The functions of human Ringo/Speedy proteins during the somatic cell cycle are discussed. To keep going with cell cycle progression and in particular with mitosis, Narumiya and Yasuda present the literature indicating that Rho GTPases, especially Cdc42, are not only involved in cytokinesis but also in spindle assembly and chromosome alignment and attachment during mitosis. The authors discuss experimental evidence for and against a role of Cdc42 in mitosis; this remains controversial even though upstream regulators www.sciencedirect.com
Editorial overview Prigent and Goud 129
and downstream effectors of Rho GTPases have been found to be involved in various stages of mitosis. While the previous reviews have described internal cellular signalling pathways, the three next papers focus on cell-to-cell signalling. Partitioning-defective 6 (PAR6) is an adaptor protein involved in cell polarity and in controlling epithelial polarity, polarized cell migration and asymmetric cell division. Together with Cdc42, whose function in mitosis was described in the previous paper, it forms multiprotein complexes. Here Bose and Wrana report how PAR6 is regulated by extracellular signals, particularly focusing on the TGFb pathway and how TGFb-dependent phosphorylation of PAR6 triggers the tight junction loss involved in epithelial-to-mesenchymal transition, which is correlated with cancer progression. The following paper by Roland Le Borgne covers the most recent advances on the endocytosis and endosomal trafficking of Notch and its ligands. Notch signalling has an evolutionarily conserved role in mediating cell–cell
www.sciencedirect.com
interactions in many different cellular contexts during development. A number of studies have shown that intracellular trafficking of the Notch receptor and its ligands are intimately connected to Notch activation. Finally, the last paper of this issue is dedicated to neurotransmission. Organization of synaptic vesicles that will be released upon depolymerisation to ensure communication between neurones is the main topic of this review. Olsen, Moore, Nicoll and Bredt provide an update on the relation between MALS/Veli family of protein and the network of interacting proteins that defines their interaction with Liprins. These proteins participate to a synaptic network that ensures efficient neurotransmission. So this issue dedicated to complexity issue finishes with a paper related to the most complex area in biology: the brain. We would like to apologize for signalling areas not covered in this issue, and for the authors whose work could not be included for reasons of space. We have tried to give a taste of major advances in cell signalling that went out this past year.
Current Opinion in Cell Biology 2006, 18:127–129