Chemotaxis: signalling the way forward

Haastert, Peter J.M. van; Devreotes, Peter N.

doi:10.1038/nrm1435

Cited by 650 publications

(594 citation statements)

References 106 publications

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“…The GPCR activation triggers actin cytoskeleton reorganization to form lamellipodia, the flattened F-actin-rich leading edge of migrating cells, which is a critical process of cancer cell metastasis (Van Haastert and Devreotes, 2004). We found that treatment with pristimerin significantly reduced the chemotactic reagentmediated lamellipodia formation in breast cancer cells in vitro.…”

Section: Discussionmentioning

confidence: 77%

Pristimerin Inhibits Breast Cancer Cell Migration by Up-regulating Regulator of G Protein Signaling 4 Expression

Mu¹,

Shi²,

Sun³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background/Aim: Pristimerin isolated from Celastrus and Maytenus spp can inhibit proteasome activity. However, whether pristimerin can modulate cancer metastasis is unknown. Methods: The impacts of pristimerin on the purified and intracellular chymotrypsin proteasomal activity, the levels of regulator of G protein signaling 4 (RGS 4) expression and breast cancer cell lamellipodia formation, and the migration and invasion were determined by enzymatic, Western blot, immunofluorescent, and transwell assays, respectively. Results: We found that pristimerin inhibited human chymotrypsin proteasomal activity in MDA-MB-231 cells in a dose-dependent manner. Pristimerin also inhibited breast cancer cell lamellipodia formation, migration, and invasion in vitro by up-regulating RGS4 expression. Thus, knockdown of RGS4 attenuated pristimerin-mediated inhibition of breast cancer cell migration and invasion. Furthermore, pristimerin inhibited growth and invasion of implanted breast tumors in mice. Conclusion: Pristmerin inhibits proteasomal activity and increases the levels of RGS4, inhibiting the migration and invasion of breast cancer cells.

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Section: Discussionmentioning

confidence: 77%

Pristimerin Inhibits Breast Cancer Cell Migration by Up-regulating Regulator of G Protein Signaling 4 Expression

Mu¹,

Shi²,

Sun³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Although a number of intracellular signalling pathways involved in the polarization and directional migration of cells have been characterized (Jones, 2000;Weiner, 2002;Van Haastert and Devreotes, 2004), relatively little is known as to how these signal transduction components are coupled to the transmembrane receptors that sense the chemotactic gradient. Previously, we have demonstrated that the CD44 S291A mutant blocks the chemotactic migration of CD44-expressing MDA-MB-435 breast cancer cells up a PMA gradient.…”

Section: Discussionmentioning

confidence: 99%

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

2006

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Cancer progression is associated with enhanced directional cell migration, both of the tumour cells invading into the stroma and stromal cells infiltrating the tumour site. In cell-based assays to study directional cell migration, phorbol esters are frequently used as a chemotactic agent. However, the molecular mechanism by which these activators of protein kinase C (PKC) result in the establishment of a polarized migratory phenotype is not known. Here we show that CD44 expression is essential for chemotaxis towards a phorbol ester gradient. In an investigation of CD44 phosphorylation kinetics in resting and stimulated cells, Ser316 was identified as a novel site of phosphorylation following activation of PKC. PKC does not phosphorylate Ser316 directly, but rather mediates the activation of downstream Ser316 kinase(s). In transfection studies, a phosphorylation-deficient Ser316 mutant was shown to act in a dominant-negative fashion to impair chemotaxis mediated by endogenous CD44 in response to a phorbol ester gradient. Importantly, this mutation had no effect on random cell motility or the ability of cells to migrate directionally towards a cocktail of chemoattractants. These studies demonstrate that CD44 functions to provide directional cues to migrating cells without affecting the motility apparatus.

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“…Chemotaxis is essential for a variety of physiological processes in mammals as well as for the survival of lower eukaryotes. The mechanisms that regulate the directed migration of neutrophils and Dictyostelium discoideum have been extensively studied previously (van Haastert and Devreotes, 2004;Bagorda et al, 2006;Friedl and Weigelin, 2008;Stephens et al, 2008). One particular challenge of these fast-moving cells is to maintain the ability to respond sensitively and rapidly to an attractant signal.…”

Section: Introductionmentioning

confidence: 99%

The Group Migration of Dictyostelium Cells Is Regulated by Extracellular Chemoattractant Degradation

Garcia

Rericha

Heger

et al. 2009

MBoC

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Starvation of Dictyostelium induces a developmental program in which cells form an aggregate that eventually differentiates into a multicellular structure. The aggregate formation is mediated by directional migration of individual cells that quickly transition to group migration in which cells align in a head-to-tail manner to form streams. Cyclic AMP acts as a chemoattractant and its production, secretion, and degradation are highly regulated. A key protein is the extracellular phosphodiesterase PdsA. In this study we examine the role and localization of PdsA during chemotaxis and streaming. We find that pdsA ؊ cells respond chemotactically to a narrower range of chemoattractant concentrations compared with wild-type (WT) cells. Moreover, unlike WT cells, pdsA ؊ cells do not form streams at low cell densities and form unusual thick and transient streams at high cell densities. We find that the intracellular pool of PdsA is localized to the endoplasmic reticulum, which may provide a compartment for storage and secretion of PdsA. Because we find that cAMP synthesis is normal in cells lacking PdsA, we conclude that signal degradation regulates the external cAMP gradient field generation and that the group migration behavior of these cells is compromised even though their signaling machinery is intact. INTRODUCTIONThe process by which cells sense an attractant molecule and respond by migrating directionally toward it is called chemotaxis. Chemotaxis is essential for a variety of physiological processes in mammals as well as for the survival of lower eukaryotes. The mechanisms that regulate the directed migration of neutrophils and Dictyostelium discoideum have been extensively studied previously (van Haastert and Devreotes, 2004;Bagorda et al., 2006;Friedl and Weigelin, 2008;Stephens et al., 2008). One particular challenge of these fast-moving cells is to maintain the ability to respond sensitively and rapidly to an attractant signal. Because both neutrophils and Dictyostelium cells use signal relay loops to propagate chemoattractant signals, mechanisms must be at play to maintain detectable levels of chemoattractants. Remarkably, signal degradation also seems to play an important role in the developmental processes of multicellular organisms. Migration of primordial germ cells in Drosophila and Zebrafish seems to require degradation of specific lysophospholipids in the former or chemokines in the latter to allow these cells to find their proper developmental environment (Renault and Lehmann, 2006;Minina et al., 2007). Many cell types use receptor-mediated degradation to maintain detectable levels of chemoattractants. In this context, cells internalize the bound receptor and as part of the receptor recycling pathway the ligand is released for degradation (Minina et al., 2007;Boldajipour et al., 2008;Borroni et al., 2008;Scola et al., 2008). Alternatively, extracellular enzymes can specifically degrade the extracellular signaling molecules, allowing the sensing machinery to go back to basal levels and retain high se...

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Chemotaxis: signalling the way forward

Cited by 650 publications

References 106 publications

Pristimerin Inhibits Breast Cancer Cell Migration by Up-regulating Regulator of G Protein Signaling 4 Expression

Pristimerin Inhibits Breast Cancer Cell Migration by Up-regulating Regulator of G Protein Signaling 4 Expression

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

The Group Migration of Dictyostelium Cells Is Regulated by Extracellular Chemoattractant Degradation

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