Reciprocal regulation of actin cytoskeleton remodelling and cell migration by Ca2+and Zn2+: role of TRPM2 channels

The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cell processes, including cell migration. Mutations in the TTC7A gene have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. Although several cellular functions have been associated with TTC7A, the role of the protein in the maintenance of the immune homeostasis is still poorly understood. Here we leverage microfabricated devices to investigate the impact of TTC7A deficiency in leukocytes migration at the single cell level. We show that TTC7A-deficient leukocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositides signaling, leading to the downregulation of the PI3K/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamic. This resulted in impaired cell motility, accumulation of DNA damage and increased cell death during chemotaxis in dense 3D gels. Our results highlight a novel role of TTC7A as a critical regulator of leukocyte migration. Impairment of this cellular function is likely to contribute to pathophysiology underlying progressive immunodeficiency in patients.

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Role of the p66Shc Isoform in Insulin-like Growth Factor I Receptor Signaling through MEK/Erk and Regulation of Actin Cytoskeleton in Rat Myoblasts

Journal of Biological Chemistry ◽

10.1074/jbc.m403936200 ◽

2004 ◽

Vol 279 (42) ◽

pp. 43900-43909 ◽

Cited By ~ 30

Author(s):

Annalisa Natalicchio ◽

Luigi Laviola ◽

Claudia De Tullio ◽

Lucia Adelaide Renna ◽

Carmela Montrone ◽

...

Keyword(s):

Growth Factor ◽

Actin Cytoskeleton ◽

Insulin Like Growth Factor ◽

Receptor Signaling ◽

Factor I ◽

Growth Factor I ◽

Regulation Of Actin Cytoskeleton

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The PKGIα/VASP pathway is involved in insulin- and high glucose-dependent regulation of albumin permeability in cultured rat podocytes

The Journal of Biochemistry ◽

10.1093/jb/mvaa059 ◽

2020 ◽

Vol 168 (6) ◽

pp. 575-588

Author(s):

Patrycja Rachubik ◽

Maria Szrejder ◽

Irena Audzeyenka ◽

Dorota Rogacka ◽

Michał Rychłowski ◽

...

Keyword(s):

Actin Cytoskeleton ◽

High Glucose ◽

Principal Component ◽

Glomerular Permeability ◽

Filtration Barrier ◽

Vasp Phosphorylation ◽

High Insulin ◽

Cytoskeleton Dynamics ◽

Regulation Of Actin Cytoskeleton

Abstract Podocytes, the principal component of the glomerular filtration barrier, regulate glomerular permeability to albumin via their contractile properties. Both insulin- and high glucose (HG)-dependent activation of protein kinase G type Iα (PKGIα) cause reorganization of the actin cytoskeleton and podocyte disruption. Vasodilator-stimulated phosphoprotein (VASP) is a substrate for PKGIα and involved in the regulation of actin cytoskeleton dynamics. We investigated the role of the PKGIα/VASP pathway in the regulation of podocyte permeability to albumin. We evaluated changes in high insulin- and/or HG-induced transepithelial albumin flux in cultured rat podocyte monolayers. Expression of PKGIα and downstream proteins was confirmed by western blot and immunofluorescence. We demonstrate that insulin and HG induce changes in the podocyte contractile apparatus via PKGIα-dependent regulation of the VASP phosphorylation state, increase VASP colocalization with PKGIα, and alter the subcellular localization of these proteins in podocytes. Moreover, VASP was implicated in the insulin- and HG-dependent dynamic remodelling of the actin cytoskeleton and, consequently, increased podocyte permeability to albumin under hyperinsulinaemic and hyperglycaemic conditions. These results indicate that insulin- and HG-dependent regulation of albumin permeability is mediated by the PKGIα/VASP pathway in cultured rat podocytes. This molecular mechanism may explain podocytopathy and albuminuria in diabetes.

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Netrin instructs synaptic vesicle clustering through Rac GTPase, MIG-10, and the actin cytoskeleton

The Journal of Cell Biology ◽

10.1083/jcb.201110127 ◽

2012 ◽

Vol 197 (1) ◽

pp. 75-88 ◽

Cited By ~ 41

Author(s):

Andrea K.H. Stavoe ◽

Daniel A. Colón-Ramos

Keyword(s):

Cell Migration ◽

Subcellular Localization ◽

Actin Cytoskeleton ◽

Axon Guidance ◽

Synaptic Vesicle ◽

Active Zone ◽

Rac Gtpase ◽

Signaling Modules

Netrin is a chemotrophic factor known to regulate a number of neurodevelopmental processes, including cell migration, axon guidance, and synaptogenesis. Although the role of Netrin in synaptogenesis is conserved throughout evolution, the mechanisms by which it instructs synapse assembly are not understood. Here we identify a mechanism by which the Netrin receptor UNC-40/DCC instructs synaptic vesicle clustering in vivo. UNC-40 localized to presynaptic regions in response to Netrin. We show that UNC-40 interacted with CED-5/DOCK180 and instructed CED-5 presynaptic localization. CED-5 in turn signaled through CED-10/Rac1 and MIG-10/Lamellipodin to organize the actin cytoskeleton in presynaptic regions. Localization of this signaling pathway to presynaptic regions was necessary for synaptic vesicle clustering during synapse assembly but not for the subcellular localization of active zone proteins. Thus, vesicle clustering and localization of active zone proteins are instructed by separate pathways downstream of Netrin. Our data indicate that signaling modules known to organize the actin cytoskeleton during guidance can be co-opted to instruct synaptic vesicle clustering.

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Role of heparan sulfate in mediating CXCL8-induced endothelial cell migration

10.7287/peerj.preprints.1421 ◽

2015 ◽

Author(s):

Zhiping Yan ◽

Jingxia Liu ◽

Linshen Xie ◽

Xiaoheng Liu ◽

Ye Zeng

Keyword(s):

Cell Migration ◽

Endothelial Cell ◽

Actin Cytoskeleton ◽

Heparan Sulfate ◽

Rho Gtpases ◽

Umbilical Vein ◽

Underlying Mechanism ◽

Endothelial Cell Migration ◽

Endothelial Glycocalyx

Several positively charged epitopes on the surface of CXCL8 involved in the binding of the major components of endothelial glycocalyx, sulfated glycosaminoglycans (GAGs).In the present study, we aimed to test the hypothesis that the surface GAGs — heparan sulfate (HS) is a crucial prerequisite for enhancement of endothelial cell migration by CXCL8, and to explore its underlying mechanism by detecting the changes in expression of Rho-GTPases and in the organization of actin cytoskeleton after enzymatic removal of HS on human umbilical vein endothelial cells (HUVECs) by using heparinase III.Our results revealed that the reduction of wound area by CXCL8 was greatly attenuated by removal of HS. The upregulations of Rho-GTPases, including Cdc42, Rac1, and RhoA by CXCL8 were suppressed by removal of HS . The polymerization and polarization of actin cytoskeleton, and the increasing of stress fibers by CXCL8 were also abolished by heparinase III. Taken together, our results demonstrated an essential role of HS in mediating CXCL8-induced endothelial cell migration, and highlighted the biological relevance of the CXCL8 and GAGs interactions in endothelial cell migration.

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Role of heparan sulfate in mediating CXCL8-induced endothelial cell migration

PeerJ ◽

10.7717/peerj.1669 ◽

2016 ◽

Vol 4 ◽

pp. e1669 ◽

Cited By ~ 9

Author(s):

Zhiping Yan ◽

Jingxia Liu ◽

Linshen Xie ◽

Xiaoheng Liu ◽

Ye Zeng

Keyword(s):

Wound Healing ◽

Endothelial Cells ◽

Cell Migration ◽

Endothelial Cell ◽

Actin Cytoskeleton ◽

Heparan Sulfate ◽

Rho Gtpases ◽

Umbilical Vein ◽

Endothelial Cell Migration

CXCL8 (Interleukin-8, IL-8) plays an important role in angiogenesis and wound healing by prompting endothelial cell migration. It has been suggested that heparan sulfate (HS) could provide binding sites on endothelial cells to retain and activate highly diffusible cytokines and inflammatory chemokines. In the present study, we aimed to test the hypothesis that HS is essential for enhancement of endothelial cell migration by CXCL8, and to explore the underlying mechanism by detecting the changes in expression and activity of Rho GTPases and in the organization of actin cytoskeleton after enzymatic removal of HS on human umbilical vein endothelial cells (HUVECs) by using heparinase III. Our results revealed that the wound healing induced by CXCL8 was greatly attenuated by removal of HS. The CXCL8-upregulated Rho GTPases including Cdc42, Rac1, and RhoA, and CXCL8-increased Rac1/Rho activity were suppressed by removal of HS. The polymerization and polarization of actin cytoskeleton, and the increasing of stress fibers induced by CXCL8 were also abolished by heparinase III. Taken together, our results demonstrated an essential role of HS in mediating CXCL8-induced endothelial cell migration, and highlighted the biological importance of the interaction between CXCL8 and heparan sulfate in wound healing.

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Role of heparan sulfate in mediating CXCL8-induced endothelial cell migration

10.7287/peerj.preprints.1421v1 ◽

2015 ◽

Author(s):

Zhiping Yan ◽

Jingxia Liu ◽

Linshen Xie ◽

Xiaoheng Liu ◽

Ye Zeng

Keyword(s):

Cell Migration ◽

Endothelial Cell ◽

Actin Cytoskeleton ◽

Heparan Sulfate ◽

Rho Gtpases ◽

Umbilical Vein ◽

Underlying Mechanism ◽

Endothelial Cell Migration ◽

Endothelial Glycocalyx

Several positively charged epitopes on the surface of CXCL8 involved in the binding of the major components of endothelial glycocalyx, sulfated glycosaminoglycans (GAGs).In the present study, we aimed to test the hypothesis that the surface GAGs — heparan sulfate (HS) is a crucial prerequisite for enhancement of endothelial cell migration by CXCL8, and to explore its underlying mechanism by detecting the changes in expression of Rho-GTPases and in the organization of actin cytoskeleton after enzymatic removal of HS on human umbilical vein endothelial cells (HUVECs) by using heparinase III.Our results revealed that the reduction of wound area by CXCL8 was greatly attenuated by removal of HS. The upregulations of Rho-GTPases, including Cdc42, Rac1, and RhoA by CXCL8 were suppressed by removal of HS . The polymerization and polarization of actin cytoskeleton, and the increasing of stress fibers by CXCL8 were also abolished by heparinase III. Taken together, our results demonstrated an essential role of HS in mediating CXCL8-induced endothelial cell migration, and highlighted the biological relevance of the CXCL8 and GAGs interactions in endothelial cell migration.

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