Leukocyte Chemotaxis
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The sequential and regulated recruitment of leukocytes into tissues by chemoattractants is essential for effective clearance of pathogens and healing. The Rho GTPases Cdc42, Rac, and Rho are important for establishing and maintaining migratory polarity. Most chemoattractants for phagocytes signal either through seven transmembrane G-protein-coupled receptors (GPCRs) or tyrosine kinase receptors. Y721 is the most important for chemotaxis because it recruits phospholipase-C-γ (PL C-γ) and the p85 subunit of class 1A PI3Ks, both of which are implicated in the initiation of chemotaxis. Several intracellular signaling complexes contribute to the polarization of phagocytes in response to chemoattractants, and they probably act together to allow optimal chemotaxis. Cdc42 is implicated in multiple types of cell polarity, including axon specification, yeast mating, and epithelial polarity. There are several PLC isoforms, of which PLCβ2 and PLCβ3 are activated by GPCR signaling in neutrophils, whereas PLCβ isoforms are activated by tyrosine kinase receptors. Polarity signals act to initiate polarization of cells, but subsequent maintenance of polarity could be achieved by Rac and Rho without the requirement for additional signals. Rho and Rac refine each other's activity during cell polarization and migration, balancing actin polymerization, cell contraction, and adhesion essential for chemotaxis. Our current understanding of chemotaxis indicates that several signaling pathways act in concert to induce cell polarization, including Cdc42, Par proteins, PAK/PIX, and PI3Ks. The design and testing of inhibitors of signal transduction molecules involved in migration and chemotaxis will be an important goal for the future.Keywords:
CDC42
Cell polarity
Cdc42, a highly conserved small GTPase of the Rho family, acts as a molecular switch to modulate a wide range of signaling pathways. Vesicle trafficking and cell polarity are two processes Cdc42 is known to regulate. Although the trafficking and polarity machineries are each well understood, how they interact to cross-regulate each other in cell polarization is still a mystery. Cdc42 is an interesting candidate that may integrate these two networks within the cell. Here we review findings on the interplay between Cdc42 and trafficking in yeast, Caenorhabditis elegans, Drosophila and mammalian cell culture systems, and discuss recent advances in our understanding of the function of Cdc42 and two of its effectors, the WASp–Arp2/3 and Par complexes, in regulating polarized traffic. Work in yeast suggests that the polarized distribution of Cdc42, which acts here as a key polarity determinant, requires input from multiple processes including endocytosis and recycling. In metazoan cells, Cdc42 can regulate several steps in the biosynthetic as well as endocytotic and recycling pathways. The recent discovery that the Par polarity complex co-operates with Cdc42 in the regulation of endocytosis and recycling opens exciting possibilities for the integration of polarity protein function and endocytotic machinery.
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Cell migration is a highly regulated event that is initiated by protrusion of the cell membrane and actin reorganization. Robo1, a single‐pass transmembrane receptor, is crucial for neuronal guidance and cell migration via activating Cdc42 GTPase. ADP‐ribosylation factor (Arf)‐like 4A (Arl4A), one of Arf small GTPases, functions in cell morphology, cell migration, and actin cytoskeleton remodelling; however, the molecular mechanisms for Arl4A in cell migration is not clear. Here, we report that Arl4A binding to Robo1 modulates cell migration via promoting Cdc42 activation. We found that Arl4A interacts with Robo1 in a GTP‐dependent manner and residual 1394‐1399 of Robo1 is both required and sufficient for this interaction. Arl4A‐Robo1 interaction is essential for Arl4A‐induced cell migration and Cdc42 activation. We also showed that Arl4A binding to Robo1 decreases the association of a Cdc42‐GAP srGAP1 to Robo1. Furthermore, Slit2/Robo1 binding decreases Arl4A‐Robo1 interaction in vivo. Thus, our study reveals a novel mechanism that Arl4A participates in Slit2/Robo1 signaling on modulating cell motility via up‐regulating Cdc42 activation. Support or Funding Information NHRI‐EX106‐10601B1
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Cell polarity is essential for cell division, cell differentiation, and most differentiated cell functions including cell migration. The small G protein Cdc42 controls cell polarity in a wide variety of cellular contexts. Although restricted localization of active Cdc42 seems to be important for its distinct functions, mechanisms responsible for the concentration of active Cdc42 at precise cortical sites are not fully understood. In this study, we show that during directed cell migration, Cdc42 accumulation at the cell leading edge relies on membrane traffic. Cdc42 and its exchange factor βPIX localize to intracytosplasmic vesicles. Inhibition of Arf6-dependent membrane trafficking alters the dynamics of Cdc42-positive vesicles and abolishes the polarized recruitment of Cdc42 and βPIX to the leading edge. Furthermore, we show that Arf6-dependent membrane dynamics is also required for polarized recruitment of Rac and the Par6–aPKC polarity complex and for cell polarization. Our results demonstrate influence of membrane dynamics on the localization and activation of Cdc42 and consequently on directed cell migration.
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Cell polarity is fundamental to the function of most cells. The evolutionarily conserved molecular machinery that controls cell polarity is centered on a family of GTPases related to Cdc42. Cdc42 becomes activated and concentrated at polarity sites, but studies in yeast model systems led to controversy on the mechanisms of polarization. Here we review recent studies that have clarified how Cdc42 becomes polarized in yeast. On one hand, findings that appeared to support a key role for the actin cytoskeleton and vesicle traffic in polarity establishment now appear to reflect the action of stress response pathways induced by cytoskeletal perturbations. On the other hand, new findings strongly support hypotheses on the polarization mechanism whose origins date back to the mathematician Alan Turing. The key features of the polarity establishment mechanism in yeasts include a positive feedback pathway in which active Cdc42 recruits a Cdc42 activator to polarity sites, and differential mobility of polarity "activators" and "substrates."
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CDC42
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Asymmetric cell division
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The Rho GTPase Cdc42 is a central regulator of cell polarity in diverse cell types. The activity of Cdc42 is dynamically controlled in time and space to enable distinct polarization events, which generally occur along a single axis in response to spatial cues. Our understanding of the mechanisms underlying Cdc42 polarization has benefited largely from studies of the budding yeast Saccharomyces cerevisiae, a genetically tractable model organism. In budding yeast, Cdc42 activation occurs in two temporal steps in the G1 phase of the cell cycle to establish a proper growth site. Here, we review findings in budding yeast that reveal an intricate crosstalk among polarity proteins for biphasic Cdc42 regulation. The first step of Cdc42 activation may determine the axis of cell polarity, while the second step ensures robust Cdc42 polarization for growth. Biphasic Cdc42 polarization is likely to ensure the proper timing of events including the assembly and recognition of spatial landmarks and stepwise assembly of a new ring of septins, cytoskeletal GTP-binding proteins, at the incipient bud site. Biphasic activation of GTPases has also been observed in mammalian cells, suggesting that biphasic activation could be a general mechanism for signal-responsive cell polarization. Cdc42 activity is necessary for polarity establishment during normal cell division and development, but its activity has also been implicated in the promotion of aging. We also discuss negative polarity signaling and emerging concepts of Cdc42 signaling in cellular aging.
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Cell polarization is a prerequisite for essential processes such as cell migration, proliferation or differentiation. The yeast Saccharomyces cerevisiae under control of the GTPase Cdc42 is able to polarize without the help of cytoskeletal structures and spatial cues through a pathway depending on its guanine nucleotide dissociation inhibitor (GDI) Rdi1. To develop a fundamental understanding of yeast polarization we establish a detailed mechanistic model of GDI-mediated polarization. We show that GDI-mediated polarization provides precise spatial and temporal control of Cdc42 signaling and give experimental evidence for our findings. Cell cycle induced changes of Cdc42 regulation enhance positive feedback loops of active Cdc42 production, and thereby allow simultaneous switch-like regulation of focused polarity and Cdc42 activation. This regulation drives the direct formation of a unique polarity cluster with characteristic narrowing dynamics, as opposed to the previously proposed competition between transient clusters. As the key components of the studied system are conserved among eukaryotes, we expect our findings also to apply to cell polarization in other organisms.
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<div>Abstract<p>The tumor suppressor LKB1 is mutated in 30% of non–small cell lung cancer (NSCLC) tumors and cell lines and is proposed to be a key regulator of epithelial cell polarity; however, how LKB1 regulates cancer cell polarity is not known. The experiments described herein show for the first time that LKB1 is a dynamic, actin-associated protein that rapidly polarizes to the leading edge of motile cancer cells. LKB1 proves to be essential for NSCLC polarity, because LKB1 depletion results in classic cell polarity defects, such as aberrant Golgi positioning, reduced lamellipodia formation, and aberrant morphology. To probe how LKB1 regulates these events, we show that LKB1 colocalizes at the cellular leading edge with two key components of the polarity pathway — the small rho GTPase cdc42 and its downstream binding partner p21-activated kinase (PAK). Importantly, LKB1 functionality is required for cdc42 polarization to the leading edge, maintaining active cdc42 levels, and downstream PAK phosphorylation. To do this, LKB1 interacts only with active form of cdc42 and PAK, but not with inactive cdc42. Taken together, these results show that LKB1 is a critical mediator of the NSCLC polarity program in lung cancer cells through a novel LKB1-cdc42-PAK pathway. [Cancer Res 2008;68(3):740–8]</p></div>
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Abstract A key feature of cells is the capacity to activate new functional polarized domains contemporaneously to pre-existing ones. How cells accomplish this is not clear. Here, we show that in fission yeast inhibition of cell polarity at pre-existing domains of polarized cell growth is required to activate new growth. This inhibition is mediated by the ERM-related polarity factor Tea3, which antagonizes the activation of the Rho-GTPase Cdc42 by its co-factor Scd2. We demonstrate that Tea3 acts in a phosphorylation-dependent manner controlled by the PAK kinase Shk1 and that, like Scd2, Tea3 is direct substrate of Shk1. Importantly, we show that Tea3 and Scd2 compete for their binding to Shk1, indicating that their biochemical competition for Shk1 underpins their antagonistic roles in controlling polarity. Thus, by preventing pre-existing growth domains from becoming overpowering, Tea3 allows cells to redistribute their polarity-activating machinery to prospective sites and control their timing of activation.
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Abstract The tumor suppressor LKB1 is mutated in 30% of non–small cell lung cancer (NSCLC) tumors and cell lines and is proposed to be a key regulator of epithelial cell polarity; however, how LKB1 regulates cancer cell polarity is not known. The experiments described herein show for the first time that LKB1 is a dynamic, actin-associated protein that rapidly polarizes to the leading edge of motile cancer cells. LKB1 proves to be essential for NSCLC polarity, because LKB1 depletion results in classic cell polarity defects, such as aberrant Golgi positioning, reduced lamellipodia formation, and aberrant morphology. To probe how LKB1 regulates these events, we show that LKB1 colocalizes at the cellular leading edge with two key components of the polarity pathway — the small rho GTPase cdc42 and its downstream binding partner p21-activated kinase (PAK). Importantly, LKB1 functionality is required for cdc42 polarization to the leading edge, maintaining active cdc42 levels, and downstream PAK phosphorylation. To do this, LKB1 interacts only with active form of cdc42 and PAK, but not with inactive cdc42. Taken together, these results show that LKB1 is a critical mediator of the NSCLC polarity program in lung cancer cells through a novel LKB1-cdc42-PAK pathway. [Cancer Res 2008;68(3):740–8]
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