scholarly journals Phosphatidylinositol 4-kinase III beta regulates cell shape, migration, and focal adhesion number

2020 ◽  
Vol 31 (17) ◽  
pp. 1904-1916
Author(s):  
Patricia Bilodeau ◽  
Daniel Jacobsen ◽  
Denise Law-Vinh ◽  
Jonathan M. Lee
Keyword(s):  
Cell Motility ◽  
Focal Adhesion ◽  
Cell Shape ◽  
Leading Edge ◽  
Lipid Kinase ◽  
Fibroblast Migration ◽  
Phosphatidylinositol 4

This work describes a role for the lipid phosphatidylinositol 4-phosphate (PI4P) and lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ) in cell motility, cell shape, and focal adhesion (FA) formation. During fibroblast migration, PI4P vesicles move to the leading edge and fuse with FA there. Deletion of PI4KIIIB impairs fibroblast migration, increases the number of FA, and alters cell shape.

scholarly journals Phosphatidylinositol 4-kinase III beta regulates cell shape, migration and Focal Adhesion number

2019 ◽  
Author(s):  
Patricia Bilodeau ◽  
Daniel Jacobsen ◽  
Denise Law-Vinh ◽  
Jonathan M Lee
Keyword(s):  
Cell Adhesion ◽  
Focal Adhesion ◽  
Cell Shape ◽  
Leading Edge ◽  
Membrane Dynamics ◽  
Breast Cancers ◽  
Cellular Functions ◽  
Lipid Kinase ◽  
Golgi Structure ◽  
Phosphatidylinositol 4

AbstractCell shape is regulated by cell adhesion and cytoskeletal and membrane dynamics. Cell shape, adhesion and motility have a complex relationship and understanding them is important in understanding developmental patterning and embryogenesis. Here we show that the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ) regulates cell shape, migration and Focal Adhesion (FA) number. PI4KIIIβ generates phosphatidylinositol 4-phosphate from phosphatidylinositol and is highly expressed in a subset of human breast cancers. PI4KIIIβ and the PI4P it generates regulate a variety of cellular functions, ranging from control of Golgi structure, fly fertility and Akt signaling. Here, we show that loss of PI4KIIIβ expression decreases cell migration and alters cell shape in NIH3T3 fibroblasts. The changes are accompanied by an increase in the number of FA in cells lacking PI4KIIIβ. Furthermore, we find that PI4P-containing vesicles move to the migratory leading-edge during migration and that some of these vesicles tether to and fuse with FA. Fusion is associated with FA disassembly. This suggests a novel regulatory role for PI4KIIIβ and PI4P in cell adhesion and cell shape maintenance.

scholarly journals Type I phosphatidylinositol 4-phosphate 5-kinase controls neutrophil polarity and directional movement

2007 ◽  
Vol 179 (7) ◽  
pp. 1539-1553 ◽  
Author(s):  
Rosa Ana Lacalle ◽  
Rosa M. Peregil ◽  
Juan Pablo Albar ◽  
Ernesto Merino ◽  
Carlos Martínez-A ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Cell Movement ◽  
Leading Edge ◽  
Cell Polarization ◽  
Type I ◽  
Lipid Kinase ◽  
Erm Proteins ◽  
Chemical Gradients ◽  
C Terminus ◽  
Phosphatidylinositol 4

Directional cell movement in response to external chemical gradients requires establishment of front–rear asymmetry, which distinguishes an up-gradient protrusive leading edge, where Rac-induced F-actin polymerization takes place, and a down-gradient retractile tail (uropod in leukocytes), where RhoA-mediated actomyosin contraction occurs. The signals that govern this spatial and functional asymmetry are not entirely understood. We show that the human type I phosphatidylinositol 4-phosphate 5-kinase isoform β (PIPKIβ) has a role in organizing signaling at the cell rear. We found that PIPKIβ polarized at the uropod of neutrophil-differentiated HL60 cells. PIPKIβ localization was independent of its lipid kinase activity, but required the 83 C-terminal amino acids, which are not homologous to other PIPKI isoforms. The PIPKIβ C terminus interacted with EBP50 (4.1-ezrin-radixin-moesin (ERM)-binding phosphoprotein 50), which enabled further interactions with ERM proteins and the Rho-GDP dissociation inhibitor (RhoGDI). Knockdown of PIPKIβ with siRNA inhibited cell polarization and impaired cell directionality during dHL60 chemotaxis, suggesting a role for PIPKIβ in these processes.

scholarly journals A Drosophila homolog of the Rac- and Cdc42-activated serine/threonine kinase PAK is a potential focal adhesion and focal complex protein that colocalizes with dynamic actin structures.

1996 ◽  
Vol 16 (5) ◽  
pp. 1896-1908 ◽  
Author(s):  
N Harden ◽  
J Lee ◽  
H Y Loh ◽  
Y M Ong ◽  
I Tan ◽  
...  
Keyword(s):  
Focal Adhesion ◽  
Cell Shape ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Epidermal Cells ◽  
Dorsal Closure ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Amino Terminal ◽  
Drosophila Homolog

Changes in cell morphology are essential in the development of a multicellular organism. The regulation of the cytoskeleton by the Rho subfamily of small GTP-binding proteins is an important determinant of cell shape. The Rho subfamily has been shown to participate in a variety of morphogenetic processes during Drosophila melanogaster development. We describe here a Drosophila homolog, DPAK, of the serine/threonine kinase PAK, a protein which is a target of the Rho subfamily proteins Rac and Cdc42. Rac, Cdc42, and PAK have previously been implicated in signaling by c-Jun amino-terminal kinases. DPAK bound to activated (GTP-bound) Drosophila Rac (DRacA) and Drosophila Cdc42. Similarities in the distributions of DPAK, integrin, and phosphotyrosine suggested an association of DPAK with focal adhesions and Cdc42- and Rac-induced focal adhesion-like focal complexes. DPAK was elevated in the leading edge of epidermal cells, whose morphological changes drive dorsal closure of the embryo. We have previously shown that the accumulation of cytoskeletal elements initiating cell shape changes in these cells could be inhibited by expression of a dominant-negative DRacA transgene. We show that leading-edge epidermal cells flanking segment borders, which express particularly large amounts of DPAK, undergo transient losses of cytoskeletal structures during dorsal closure. We propose that DPAK may be regulating the cytoskeleton through its association with focal adhesions and focal complexes and may be participating with DRacA in a c-Jun amino-terminal kinase signaling pathway recently demonstrated to be required for dorsal closure.

scholarly journals Pak1 regulates focal adhesion strength, myosin IIA distribution, and actin dynamics to optimize cell migration

2011 ◽  
Vol 193 (7) ◽  
pp. 1289-1303 ◽  
Author(s):  
Violaine D. Delorme-Walker ◽  
Jeffrey R. Peterson ◽  
Jonathan Chernoff ◽  
Clare M. Waterman ◽  
Gaudenz Danuser ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Adhesion Strength ◽  
Focal Adhesion ◽  
Leading Edge ◽  
Actin Dynamics ◽  
Filamentous Actin ◽  
Downstream Effectors ◽  
Myosin Iia ◽  
And Migration

Cell motility requires the spatial and temporal coordination of forces in the actomyosin cytoskeleton with extracellular adhesion. The biochemical mechanism that coordinates filamentous actin (F-actin) assembly, myosin contractility, adhesion dynamics, and motility to maintain the balance between adhesion and contraction remains unknown. In this paper, we show that p21-activated kinases (Paks), downstream effectors of the small guanosine triphosphatases Rac and Cdc42, biochemically couple leading-edge actin dynamics to focal adhesion (FA) dynamics. Quantitative live cell microscopy assays revealed that the inhibition of Paks abolished F-actin flow in the lamella, displaced myosin IIA from the cell edge, and decreased FA turnover. We show that, by controlling the dynamics of these three systems, Paks regulate the protrusive activity and migration of epithelial cells. Furthermore, we found that expressing Pak1 was sufficient to overcome the inhibitory effects of excess adhesion strength on cell motility. These findings establish Paks as critical molecules coordinating cytoskeletal systems for efficient cell migration.

scholarly journals Multiplexed quantitative screens of single cell shape and YAP/TAZ localisation identify DOCK5 as a coincident detector of polarity and adhesion during migration

2020 ◽  
Author(s):  
Patricia Pascual-Vargas ◽  
Mar Arias-Garcia ◽  
Theodoros I. Roumeliotis ◽  
Jyoti S. Choudhary ◽  
Chris Bakal
Keyword(s):  
Breast Cancer ◽  
Focal Adhesion ◽  
Cell Shape ◽  
Triple Negative ◽  
Leading Edge ◽  
Genetic Interactions ◽  
Genetic Screens ◽  
Protein Levels ◽  
Quantitative Genetic ◽  
Metastatic Cells

AbstractYAP and TAZ are transcriptional co-activators that are often constitutively active in triple negative breast cancer (TNBC) cells driving proliferation, invasion, and drug resistance. Through multiplexed quantitative genetic screens for YAP/TAZ localisation and cell shape, we found that the RhoGEF DOCK5 is essential for YAP/TAZ activation in metastatic cells and is required for the maintenance of polarity during migration. DOCK5 regulates cell shape and thus YAP/TAZ through different genetic interactions with CDC42, RAC, and RHOA GTPases. DOCK5 regulates focal adhesion (FA) morphogenesis in RAC-dependent fashions that promote RHOA mediated actomyosin engagement of FA. Using unbiased systems-level quantification of protein levels by mass spectrometry we show that DOCK5 maintains polarity by stabilising protein levels of the CDC42 effector GSK3β. We conclude DOCK5 acts as a coincidence detector to promote leading edge persistence in subcellular locations where there is both RAC and RHOA dependent FA morphogenesis and active CDC42 mediated cell polarisation.

NO alters cell shape and motility in aortic smooth muscle cells via protein tyrosine phosphatase 1B activation

1999 ◽  
Vol 277 (3) ◽  
pp. H1014-H1026 ◽  
Author(s):  
Aviv Hassid ◽  
Jian Yao ◽  
Shile Huang
Keyword(s):  
Cell Motility ◽  
Focal Adhesion ◽  
Protein Tyrosine Phosphatase ◽  
Cell Shape ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B ◽  
Aortic Smooth Muscle ◽  
Focal Adhesion Proteins ◽  
And Migration ◽  
Ptp 1B

Cell motility is an important determinant of vascular disease. We examined mechanisms underlying the effect of nitric oxide (NO) on motility in cultured primary aortic smooth muscle cells from newborn rats. The NO donor S-nitroso- N-acetyl-penicillamine (SNAP) increased the activity of protein tyrosine phosphatase 1B (PTP-1B). This effect was mimicked by a cGMP analog and blocked by the guanyl cyclase antagonist 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, indicating the involvement of cGMP. Treatment of cells with antisense, but not control oligodeoxynucleotide (ODN), against PTP-1B attenuated the inhibitory effect of NO on cell motility. Cell shape and adhesion are important determinants of cell motility. We report that SNAP induced cell rounding and reduced adhesion and caused dissociation of actin stress fibers. Moreover, SNAP reduced phosphotyrosine levels in focal adhesion proteins, paxillin, and focal adhesion kinase. The PTP inhibitor phenylarsine oxide or decrease of PTP-1B protein levels via the use of antisense ODN prevented NO-induced cell-shape change, altered adhesion, and migration. These results indicate that NO regulates cell shape, adhesion, and migration by dephosphorylation of focal adhesion proteins via a mechanism that requires PTP-1B activity.

scholarly journals Nascent Focal Adhesions Are Responsible for the Generation of Strong Propulsive Forces in Migrating Fibroblasts

2001 ◽  
Vol 153 (4) ◽  
pp. 881-888 ◽  
Author(s):  
Karen A. Beningo ◽  
Micah Dembo ◽  
Irina Kaverina ◽  
J. Victor Small ◽  
Yu-li Wang
Keyword(s):  
Focal Adhesion ◽  
Fluorescent Protein ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Time Lapse ◽  
Fibroblast Migration ◽  
Motile Cells ◽  
Green Fluorescent ◽  
Traction Stress

Fibroblast migration involves complex mechanical interactions with the underlying substrate. Although tight substrate contact at focal adhesions has been studied for decades, the role of focal adhesions in force transduction remains unclear. To address this question, we have mapped traction stress generated by fibroblasts expressing green fluorescent protein (GFP)-zyxin. Surprisingly, the overall distribution of focal adhesions only partially resembles the distribution of traction stress. In addition, detailed analysis reveals that the faint, small adhesions near the leading edge transmit strong propulsive tractions, whereas large, bright, mature focal adhesions exert weaker forces. This inverse relationship is unique to the leading edge of motile cells, and is not observed in the trailing edge or in stationary cells. Furthermore, time-lapse analysis indicates that traction forces decrease soon after the appearance of focal adhesions, whereas the size and zyxin concentration increase. As focal adhesions mature, changes in structure, protein content, or phosphorylation may cause the focal adhesion to change its function from the transmission of strong propulsive forces, to a passive anchorage device for maintaining a spread cell morphology.

scholarly journals The Lipid Kinase Phosphatidylinositol-4 Kinase III Alpha Regulates the Phosphorylation Status of Hepatitis C Virus NS5A

2013 ◽  
Vol 9 (5) ◽  
pp. e1003359 ◽  
Author(s):  
Simon Reiss ◽  
Christian Harak ◽  
Inés Romero-Brey ◽  
Danijela Radujkovic ◽  
Rahel Klein ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Lipid Kinase ◽  
Phosphatidylinositol 4

EGF receptor regulation of cell motility: EGF induces disassembly of focal adhesions independently of the motility-associated PLCgamma signaling pathway

1998 ◽  
Vol 111 (5) ◽  
pp. 615-624 ◽  
Author(s):  
H. Xie ◽  
M.A. Pallero ◽  
K. Gupta ◽  
P. Chang ◽  
M.F. Ware ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Motility ◽  
Map Kinase ◽  
Signaling Pathway ◽  
Focal Adhesion ◽  
Kinase Activity ◽  
Egf Receptor ◽  
Focal Adhesions ◽  
Short Term ◽  
Egfr Kinase

A current model of growth factor-induced cell motility invokes integration of diverse biophysical processes required for cell motility, including dynamic formation and disruption of cell/substratum attachments along with extension of membrane protrusions. To define how these biophysical events are actuated by biochemical signaling pathways, we investigate here whether epidermal growth factor (EGF) induces disruption of focal adhesions in fibroblasts. We find that EGF treatment of NR6 fibroblasts presenting full-length WT EGF receptors (EGFR) reduces the fraction of cells presenting focal adhesions from approximately 60% to approximately 30% within 10 minutes. The dose dependency of focal adhesion disassembly mirrors that for EGF-enhanced cell motility, being noted at 0.1 nM EGF. EGFR kinase activity is required as cells expressing two kinase-defective EGFR constructs retain their focal adhesions in the presence of EGF. The short-term (30 minutes) disassembly of focal adhesions is reflected in decreased adhesiveness of EGF-treated cells to substratum. We further examine here known motility-associated pathways to determine whether these contribute to EGF-induced effects. We have previously demonstrated that phospholipase C(gamma) (PLCgamma) activation and mobilization of gelsolin from a plasma membrane-bound state are required for EGFR-mediated cell motility. In contrast, we find here that short-term focal adhesion disassembly is induced by a signaling-restricted truncated EGFR (c'973) which fails to activate PLCgamma or mobilize gelsolin. The PLC inhibitor U73122 has no effect on this process, nor is the actin severing capacity of gelsolin required as EGF treatment reduces focal adhesions in gelsolin-devoid fibroblasts, further supporting the contention that focal adhesion disassembly is signaled by a pathway distinct from that involving PLCgamma. Because both WT and c'973 EGFR activate the erk MAP kinase pathway, we additionally explore here this signaling pathway, not previously associated with growth factor-induced cell motility. Levels of the MEK inhibitor PD98059 that block EGF-induced mitogenesis and MAP kinase phosphorylation also abrogate EGF-induced focal adhesion disassembly and cell motility. In summary, we characterize for the first time the ability of EGFR kinase activity to directly stimulate focal adhesion disassembly and cell/substratum detachment, in relation to its ability to stimulate migration. Furthermore, we propose a model of EGF-induced motogenic cell responses in which the PLCgamma pathway stimulating cell motility is distinct from the MAP kinase-dependent signaling pathway leading to disassembly and reorganization of cell-substratum adhesion.

scholarly journals Actin-inspired feedback couples speed and persistence in a Cellular Potts Model of cell migration

2018 ◽  
Author(s):  
Inge M. N. Wortel ◽  
Ioana Niculescu ◽  
P. Martijn Kolijn ◽  
Nir Gov ◽  
Rob J. de Boer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Potts Model ◽  
Cell Shape ◽  
Computational Models ◽  
Fundamental Property ◽  
Cellular Potts Model ◽  
Universal Coupling ◽  
Migrating Cells

ABSTRACTCell migration is astoundingly diverse. Molecular signatures, cell-cell and cell-matrix interactions, and environmental structures each play their part in shaping cell motion, yielding numerous different cell morphologies and migration modes. Nevertheless, in recent years, a simple unifying law was found to describe cell migration across many different cell types and contexts: faster cells turn less frequently. Given this universal coupling between speed and persistence (UCSP), from a modelling perspective it is important to know whether computational models of cell migration capture this speed-persistence link. Here, we present an in-depth characterisation of an existing Cellular Potts Model (CPM). We first show that this model robustly reproduces the UCSP without having been designed for this task. Instead, we show that this fundamental law of migration emerges spontaneously through a crosstalk of intracellular mechanisms, cell shape, and environmental constraints, resembling the dynamic nature of cell migration in vivo. Our model also reveals how cell shape dynamics can further constrain cell motility by limiting both the speed and persistence a cell can reach, and how a rigid environment such as the skin can restrict cell motility even further. Our results further validate the CPM as a model of cell migration, and shed new light on the speed-persistence coupling that has emerged as a fundamental property of migrating cells.SIGNIFICANCEThe universal coupling between speed and persistence (UCSP) is the first general quantitative law describing motility patterns across the versatile spectrum of migrating cells. Here, we show – for the first time – that this migration law emerges spontaneously in an existing, highly popular computational model of cell migration. Studying the UCSP in entirely different model frameworks, not explicitly built with this law in mind, can help uncover how intracellular dynamics, cell shape, and environment interact to produce the diverse motility patterns observed in migrating cells.

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