G protein-coupled receptors stimulation and the control of cell migration.
TL;DR: The role of GPCR mediated signal transduction and their importance in the regulation of actin remodeling leading to cell migration are reviewed.
About: This article is published in Cellular Signalling.The article was published on 2009-07-01. It has received 238 citations till now. The article focuses on the topics: Actin remodeling & Actin cytoskeleton.
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TL;DR: The discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors induces the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics stimulated research to better understand the actin–MRTF–SRF circuit.
Abstract: Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actin-MRTF-SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity.
875 citations
TL;DR: It is demonstrated that a Rab5-to-Rac circuitry controls the morphology of motile mammalian tumor cells and primordial germinal cells during zebrafish development, suggesting that this circuitry is relevant for the regulation of migratory programs in various cells, in both in vitro settings and whole organisms.
430 citations
TL;DR: Elevated metabolism, weakened cell-to-capillary diffusive coupling, and adaptations involving H+/H+-equivalent transporters and extracellular-facing CAs give cancer cells the means to manipulate micro-environmental acidity, a cancer hallmark.
Abstract: Cell survival is conditional on the maintenance of a favourable acid–base balance (pH). Owing to intensive respiratory CO2 and lactic acid production, cancer cells are exposed continuously to large...
401 citations
TL;DR: Results indicate that the lipid raft adaptor p18 is essential for anchoring the MEK–ERK pathway to late endosomes, and shed new light on a role of endosomal MEK- ERK pathway in controlling endosome dynamics.
Abstract: The regulation of endosome dynamics is crucial for fundamental cellular functions, such as nutrient intake/digestion, membrane protein cycling, cell migration and intracellular signalling. Here, we show that a novel lipid raft adaptor protein, p18, is involved in controlling endosome dynamics by anchoring the MEK1–ERK pathway to late endosomes. p18 is anchored to lipid rafts of late endosomes through its N-terminal unique region. p18−/− mice are embryonic lethal and have severe defects in endosome/lysosome organization and membrane protein transport in the visceral endoderm. p18−/− cells exhibit apparent defects in endosome dynamics through perinuclear compartment, such as aberrant distribution and/or processing of lysosomes and impaired cycling of Rab11-positive recycling endosomes. p18 specifically binds to the p14–MP1 complex, a scaffold for MEK1. Loss of p18 function excludes the p14–MP1 complex from late endosomes, resulting in a downregulation of the MEK–ERK activity. These results indicate that the lipid raft adaptor p18 is essential for anchoring the MEK–ERK pathway to late endosomes, and shed new light on a role of endosomal MEK–ERK pathway in controlling endosome dynamics.
321 citations
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...Furthermore, the apical sur- face scavenger receptors cubilin and megalin (Christensen and Birn, 2002) were predominantly intracellular in the mutant VE cells (Figure 2F)....
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TL;DR: Synergistic interactions between matrix remodeling and tumor hypoxia influence common mechanisms that maximize tumor progression and cooperate to drive metastasis, which should identify novel therapeutic targets.
Abstract: Tumor progression ensues within a three-dimensional microenvironment that consists of cellular and non-cellular components. The extracellular matrix (ECM) and hypoxia are two non-cellular components that potently influence metastasis. ECM remodeling and collagen cross-linking stiffen the tissue stroma to promote transformation, tumor growth, motility and invasion, enhance cancer cell survival, enable metastatic dissemination, and facilitate the establishment of tumor cells at distant sites. Matrix degradation can additionally promote malignant progression and metastasis. Tumor hypoxia is functionally linked to altered stromal-epithelial interactions. Hypoxia additionally induces the expression of pro-migratory, survival and invasion genes, and up-regulates expression of ECM components and modifying enzymes, to enhance tumor progression and metastasis. Synergistic interactions between matrix remodeling and tumor hypoxia influence common mechanisms that maximize tumor progression and cooperate to drive metastasis. Thus, clarifying the molecular pathways by which ECM remodeling and tumor hypoxia intersect to promote tumor progression should identify novel therapeutic targets.
304 citations
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TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
TL;DR: It is reported that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases and their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis.
Abstract: Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.
5,132 citations
TL;DR: Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells and their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant.
Abstract: Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells. They are known principally for their pivotal role in regulating the actin cytoskeleton, but their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant. Underlying this biological complexity is a simple biochemical idea, namely that by switching on a single GTPase, several distinct signalling pathways can be coordinately activated. With spatial and temporal activation of multiple switches factored in, it is not surprising to find Rho GTPases having such a prominent role in eukaryotic cell biology.
4,616 citations
TL;DR: It is reported here that cdc42, another member of the rho family, triggers the formation of a third type of actin-based structure found at the cell periphery, filopodia, in addition to stress fibers, and rho controls the assembly of focal adhesion complexes.
4,440 citations
TL;DR: It is proposed that rac and rho are essential components of signal transduction pathways linking growth factors to the organization of polymerized actin and that growth factors act through rac to stimulate this rho-dependent response.
3,294 citations