scholarly journals Cooperative recruitment of Arl4A and Pak1 to the plasma membrane contributes to sustained Pak1 activation for cell migration

2020 ◽  
Vol 133 (3) ◽  
pp. jcs233361 ◽  
Author(s):  
Kuan-Jung Chen ◽  
Tsai-Chen Chiang ◽  
Chia-Jung Yu ◽  
Fang-Jen S. Lee
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Pak1 Activation

scholarly journals Inhibition by Thyroid Hormones of Cell Migration Activated by IGF-1 and MCP-1 in THP-1 Monocytes: Focus on Signal Transduction Events Proximal to Integrin αvβ3

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena Candelotti ◽  
Roberto De Luca ◽  
Roberto Megna ◽  
Mariangela Maiolo ◽  
Paolo De Vito ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Plasma Membrane ◽  
Cell Migration ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Integrin Αvβ3 ◽  
Membrane Receptor ◽  
Αvβ3 Integrin ◽  
Plasma Membrane Receptor ◽  
Cell Migration And Proliferation

Interaction between thyroid hormones and the immune system is reported in the literature. Thyroid hormones, thyroxine, T4, but also T3, act non-genomically through mechanisms that involve a plasma membrane receptor αvβ3 integrin, a co-receptor for insulin-like growth factor-1 (IGF-1). Previous data from our laboratory show a crosstalk between thyroid hormones and IGF-1 because thyroid hormones inhibit the IGF-1-stimulated glucose uptake and cell proliferation in L-6 myoblasts, and the effects are mediated by integrin αvβ3. IGF-1 also behaves as a chemokine, being an important factor for tissue regeneration after damage. In the present study, using THP-1 human leukemic monocytes, expressing αvβ3 integrin in their cell membrane, we focused on the crosstalk between thyroid hormones and either IGF-1 or monocyte chemoattractant protein-1 (MCP-1), studying cell migration and proliferation stimulated by the two chemokines, and the role of αvβ3 integrin, using inhibitors of αvβ3 integrin and downstream pathways. Our results show that IGF-1 is a potent chemoattractant in THP-1 monocytes, stimulating cell migration, and thyroid hormone inhibits the effect through αvβ3 integrin. Thyroid hormone also inhibits IGF-1-stimulated cell proliferation through αvβ3 integrin, an example of a crosstalk between genomic and non-genomic effects. We also studied the effects of thyroid hormone on cell migration and proliferation induced by MCP-1, together with the pathways involved, by a pharmacological approach and docking simulation. Our findings show a different downstream signaling for IGF-1 and MCP-1 in THP-1 monocytes mediated by the plasma membrane receptor of thyroid hormones, integrin αvβ3.

scholarly journals Ezrin Phosphorylation at T567 Modulates Cell Migration, Mechanical Properties, and Cytoskeletal Organization

2020 ◽  
Vol 21 (2) ◽  
pp. 435 ◽  
Author(s):  
Xiaoli Zhang ◽  
Luis R. Flores ◽  
Michael C. Keeling ◽  
Kristina Sliogeryte ◽  
Núria Gavara
Keyword(s):  
Mechanical Properties ◽  
Plasma Membrane ◽  
Cell Migration ◽  
Intracellular Localization ◽  
Dominant Negative ◽  
Cell Stiffness ◽  
Cell Cortex ◽  
Image Quantification ◽  
Cytoskeleton Organization ◽  
Nuclear Changes

Ezrin, a member of the ERM (ezrin/radixin/moesin) family of proteins, serves as a crosslinker between the plasma membrane and the actin cytoskeleton. By doing so, it provides structural links to strengthen the connection between the cell cortex and the plasma membrane, acting also as a signal transducer in multiple pathways during migration, proliferation, and endocytosis. In this study, we investigated the role of ezrin phosphorylation and its intracellular localization on cell motility, cytoskeleton organization, and cell stiffness, using fluorescence live-cell imaging, image quantification, and atomic force microscopy (AFM). Our results show that cells expressing constitutively active ezrin T567D (phosphomimetic) migrate faster and in a more directional manner, especially when ezrin accumulates at the cell rear. Similarly, image quantification results reveal that transfection with ezrin T567D alters the cell’s gross morphology and decreases cortical stiffness. In contrast, constitutively inactive ezrin T567A accumulates around the nucleus, and although it does not impair cell migration, it leads to a significant buildup of actin fibers, a decrease in nuclear volume, and an increase in cytoskeletal stiffness. Finally, cell transfection with the dominant negative ezrin FERM domain induces significant morphological and nuclear changes and affects actin, microtubules, and the intermediate filament vimentin, resulting in cytoskeletal fibers that are longer, thicker, and more aligned. Collectively, our results suggest that ezrin’s phosphorylation state and its intracellular localization plays a pivotal role in cell migration, modulating also biophysical properties, such as membrane–cortex linkage, cytoskeletal and nuclear organization, and the mechanical properties of cells.

scholarly journals CD13 tethers the IQGAP1-ARF6-EFA6 complex to the plasma membrane to promote ARF6 activation, β1 integrin recycling, and cell migration

2019 ◽  
Vol 12 (579) ◽  
pp. eaav5938 ◽  
Author(s):  
Mallika Ghosh ◽  
Robin Lo ◽  
Ivan Ivic ◽  
Brian Aguilera ◽  
Veneta Qendro ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Attachment ◽  
Leading Edge ◽  
Small Gtpase ◽  
Β1 Integrin ◽  
Recycling Endosomes ◽  
Cellular Processes ◽  
Early Endosomes

Cell attachment to the extracellular matrix (ECM) requires a balance between integrin internalization and recycling to the surface that is mediated by numerous proteins, emphasizing the complexity of these processes. Upon ligand binding in various cells, the β1 integrin is internalized, traffics to early endosomes, and is returned to the plasma membrane through recycling endosomes. This trafficking process depends on the cyclical activation and inactivation of small guanosine triphosphatases (GTPases) by their specific guanine exchange factors (GEFs) and their GTPase-activating proteins (GAPs). In this study, we found that the cell surface antigen CD13, a multifunctional transmembrane molecule that regulates cell-cell adhesion and receptor-mediated endocytosis, also promoted cell migration and colocalized with β1 integrin at sites of cell adhesion and at the leading edge. A lack of CD13 resulted in aberrant trafficking of internalized β1 integrin to late endosomes and its ultimate degradation. Our data indicate that CD13 promoted ARF6 GTPase activity by positioning the ARF6-GEF EFA6 at the cell membrane. In migrating cells, a complex containing phosphorylated CD13, IQGAP1, GTP-bound (active) ARF6, and EFA6 at the leading edge promoted the ARF6 GTPase cycling and cell migration. Together, our findings uncover a role for CD13 in the fundamental cellular processes of receptor recycling, regulation of small GTPase activities, cell-ECM interactions, and cell migration.

scholarly journals Activated Ezrin Promotes Cell Migration through Recruitment of the GEF Dbl to Lipid Rafts and Preferential Downstream Activation of Cdc42

2007 ◽  
Vol 18 (8) ◽  
pp. 2935-2948 ◽  
Author(s):  
Soren Prag ◽  
Maddy Parsons ◽  
Melanie D. Keppler ◽  
Simon M. Ameer-Beg ◽  
Paul Barber ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Lipid Raft ◽  
Rho Gtpase ◽  
Actin Binding ◽  
Fluorescence Lifetime Imaging ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Lipid Raft Microdomains

Establishment of polarized cell morphology is a critical factor for migration and requires precise spatial and temporal activation of the Rho GTPases. Here, we describe a novel role of the actin-binding ezrin/radixin/moesin (ERM)-protein ezrin to be involved in recruiting Cdc42, but not Rac1, to lipid raft microdomains, as well as the subsequent activation of this Rho GTPase and the downstream effector p21-activated kinase (PAK)1, as shown by fluorescence lifetime imaging microscopy. The establishment of a leading plasma membrane and the polarized morphology necessary for random migration are also dependent on ERM function and Cdc42 in motile breast carcinoma cells. Mechanistically, we show that the recruitment of the ERM-interacting Rho/Cdc42-specific guanine nucleotide exchange factor Dbl to the plasma membrane and to lipid raft microdomains requires the phosphorylated, active conformer of ezrin, which serves to tether the plasma membrane or its subdomains to the cytoskeleton. Together these data suggest a mechanism whereby precise spatial guanine nucleotide exchange of Cdc42 by Dbl is dependent on functional ERM proteins and is important for directional cell migration.

scholarly journals Type I PIPK-α regulates directed cell migration by modulating Rac1 plasma membrane targeting and activation

2010 ◽  
Vol 190 (3) ◽  
pp. 479-479
Author(s):  
Wei-Ting Chao ◽  
Alexes C. Daquinag ◽  
Felicity Ashcroft ◽  
Jeannette Kunz
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Membrane Targeting ◽  
Type I ◽  
Directed Cell Migration

scholarly journals IFT20 Mediates the Transport of Cell Migration Regulators From the Trans-Golgi Network to the Plasma Membrane in Breast Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Huihui Yang ◽  
Fan Zhang ◽  
Huan Long ◽  
Yiwen Lin ◽  
Jiahui Liao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Membrane ◽  
Cell Migration ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Intracellular Transport ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Trans Golgi Network ◽  
Golgi Network

IFT20 is a subunit of the intraflagellar transport (IFT) system essential for the formation and function of cilia. Besides predominant research in the cilia field, some IFT subunits perform extraciliary roles in non-ciliated cancer cells. However, the specific roles of IFT subunits in tumorigenesis remain unknown. Here, we found that knockout of IFT20 in mouse breast cancer cells lacking primary cilia promoted epithelial mesenchymal transitions (EMTs), active lamellipodia formation, and cell migration. IFT20 localized at the trans-Golgi and trans-Golgi network (TGN), and displayed vesicular co-distributions with Rab8a, the marker of TGN-to-plasma membrane vesicular trafficking. Proximity-dependent biotin identification (BioID) and colocalization analyzes showed that Numb and Ctnnal1, whose depletion promoted cell migration, co-localized with IFT20 at the trans-Golgi/TGN or intracellular transport vesicles. Furthermore, Strep-Tactin pulldown assays revealed an interaction between IFT20 and Ctnnal1 or Numb. Loss of IFT20 lowered the expression of actin-associated Tagln2, whose knockdown promoted cell migration. Thus, the extraciliary function of ITF20 in breast cancer cell was associated with the negative regulation of migration.

scholarly journals Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ryan S D'Souza ◽  
Jun Y Lim ◽  
Alper Turgut ◽  
Kelly Servage ◽  
Junmei Zhang ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Calcium Channels ◽  
Lipid Transfer Protein ◽  
Calcium Influx ◽  
Focal Adhesions ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Contact Sites ◽  
Lipid Exchange

Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca2+ influx, however our understanding of this process remains incomplete. Here, we show that Ca2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca2+-activated GEF IQSec1, and that both IQSec1 and Arf5 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid transfer protein ORP3, and that Ca2+ influx triggers PKC-dependent translocation of this complex to ER/plasma membrane (PM) contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell migration.

scholarly journals The glycolysis regulator PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma

2020 ◽  
Author(s):  
Méghane Sittewelle ◽  
Déborah Lécuyer ◽  
Anne H. Monsoro-Burq
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Melanoma Cell ◽  
Protein Interactions ◽  
Cancer Metastasis ◽  
Human Cancer ◽  
Akt Signaling ◽  
List Type ◽  
Cell Parameters ◽  
Cancer Hallmarks

AbstractCell migration is a complex process, tightly regulated during embryonic development and abnormally activated during cancer metastasis. RAS-dependent signaling is a major nexus controlling essential cell parameters such as proliferation, survival and migration using downstream effectors among which the PI3K/AKT signaling. In melanoma, oncogenic mutations frequently enhance RAS, PI3K/AKT or MAP kinase signaling, in addition to other cancer hallmarks including the activation of metabolism regulators such as PFKFB4, a critical regulator of glycolysis and Warburg effect. Here, we explore a novel function of PFKFB4 in melanoma cell migration. We find that instead of acting as a kinase as recorded in glycolysis, PFKFB4 interacts with ICMT, a post-translational modifier of RAS. PFKFB4 promotes ICMT/RAS interaction, controls RAS addressing at the plasma membrane, activates AKT signaling and enhances cell migration. We thus evidence a novel glycolysis-independent function of PFKFB4 in human cancer cells. This unconventional activity links the metabolic regulator PFKFB4 to RAS-AKT signaling and impacts melanoma cell migration.Highlights- PFKFB4, a known regulator of glycolysis, displays an unconventional role in melanoma cell migration.- PFKFB4 interacts with ICMT by protein-protein interactions and promotes RAS addressing at the plasma membrane.- PFKFB4 and ICMT cooperation modulates AKT signaling and controls melanoma cell migration.

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