scholarly journals αvβ3 and α5β1 integrin recycling pathways dictate downstream Rho kinase signaling to regulate persistent cell migration

2007 ◽  
Vol 177 (3) ◽  
pp. 515-525 ◽  
Author(s):  
Dominic P. White ◽  
Patrick T. Caswell ◽  
Jim C. Norman
Keyword(s):  
Cell Migration ◽  
Rho Kinase ◽  
Cell Movement ◽  
Αvβ3 Integrin ◽  
Protein Kinase D1 ◽  
Fibroblast Migration ◽  
Short Loop ◽  
Cell Front ◽  
Α5β1 Integrin ◽  
Persistent Cell

Accumulating evidence suggests that integrin recycling regulates cell migration. However, the lack of reagents to selectively target the trafficking of individual heterodimers, as opposed to endocytic transport as a whole, has made it difficult to define the contribution made by particular recycling pathways to directional cell movement. We show that autophosphorylation of protein kinase D1 (PKD1) at Ser916 is necessary for its association with αvβ3 integrin. Expression of PKD1916A or the use of mutants of β3 that do not bind to PKD1 selectively inhibits short-loop, Rab4-dependent recycling of αvβ3, and this suppresses the persistence of fibroblast migration. However, we report that short-loop recycling does not directly contribute to fibroblast migration by moving αvβ3 to the cell front, but by antagonizing α5β1 recycling, which, in turn, influences the cell's decision to migrate with persistence or to move randomly.

scholarly journals Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility

2006 ◽  
Vol 176 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Erik Sahai ◽  
Raquel Garcia-Medina ◽  
Jacques Pouysségur ◽  
Emmanuel Vial
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Rho Gtpases ◽  
Rho Kinase ◽  
Cell Movement ◽  
Leading Edge ◽  
Cell Periphery ◽  
Tumor Cell Migration ◽  
Tumor Cell Motility

Rho GTPases participate in various cellular processes, including normal and tumor cell migration. It has been reported that RhoA is targeted for degradation at the leading edge of migrating cells by the E3 ubiquitin ligase Smurf1, and that this is required for the formation of protrusions. We report that Smurf1-dependent RhoA degradation in tumor cells results in the down-regulation of Rho kinase (ROCK) activity and myosin light chain 2 (MLC2) phosphorylation at the cell periphery. The localized inhibition of contractile forces is necessary for the formation of lamellipodia and for tumor cell motility in 2D tissue culture assays. In 3D invasion assays, and in in vivo tumor cell migration, the inhibition of Smurf1 induces a mesenchymal–amoeboid–like transition that is associated with a more invasive phenotype. Our results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling.

Persistent cell migration emerges from a coupling between protrusion dynamics and polarized trafficking

2021 ◽  
Author(s):  
Kotryna Vaidžiulytė ◽  
Anne-Sophie Macé ◽  
Aude Battistella ◽  
William Beng ◽  
Kristine Schauer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Live Cell Imaging ◽  
Cell Movement ◽  
Intrinsic Activity ◽  
Internal Cell ◽  
Polarized Trafficking ◽  
Cell Organization ◽  
Quantitative Properties ◽  
Long Timescales ◽  
Persistent Cell

AbstractMigrating cells present a variety of paths, from random to highly directional ones. While random movement can be explained by basal intrinsic activity, persistent movement requires stable polarization. Here, we quantitatively address emergence of persistent migration in RPE1 cells over long timescales. By live-cell imaging and dynamic micropatterning, we demonstrate that the Nucleus-Golgi axis aligns with direction of migration leading to efficient cell movement. We show that polarized trafficking is directed towards protrusions with a 20 min delay, and that migration becomes random after disrupting internal cell organization. Eventually, we prove that localized optogenetic Cdc42 activation orients the Nucleus-Golgi axis. Our work suggests that polarized trafficking stabilizes the protrusive activity of the cell, while protrusive activity orients this polarity axis, leading to persistent cell migration. Using a minimal physical model, we show that this feedback is sufficient to recapitulate the quantitative properties of cell migration in the timescale of hours.

scholarly journals Protein Kinase D1 Regulates VEGF-A-Induced αvβ3 Integrin Trafficking and Endothelial Cell Migration

Traffic ◽  
2010 ◽  
Vol 11 (8) ◽  
pp. 1107-1118 ◽  
Author(s):  
Laura Di Blasio ◽  
Sara Droetto ◽  
Jim Norman ◽  
Federico Bussolino ◽  
Luca Primo
Keyword(s):  
Cell Migration ◽  
Endothelial Cell ◽  
Protein Kinase ◽  
Endothelial Cell Migration ◽  
Αvβ3 Integrin ◽  
Protein Kinase D1

scholarly journals Rab-coupling protein coordinates recycling of α5β1 integrin and EGFR1 to promote cell migration in 3D microenvironments

2008 ◽  
Vol 183 (1) ◽  
pp. 143-155 ◽  
Author(s):  
Patrick T. Caswell ◽  
May Chan ◽  
Andrew J. Lindsay ◽  
Mary W. McCaffrey ◽  
David Boettiger ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Tumor Cells ◽  
Three Dimensional ◽  
Αvβ3 Integrin ◽  
Two Dimensional ◽  
Adhesive Bonds ◽  
Promote Cell Migration ◽  
Cell Front ◽  
Coupling Protein ◽  
Α5β1 Integrin

Here we show that blocking the adhesive function of αvβ3 integrin with soluble RGD ligands, such as osteopontin or cilengitide, promoted association of Rab-coupling protein (RCP) with α5β1 integrin and drove RCP-dependent recycling of α5β1 to the plasma membrane and its mobilization to dynamic ruffling protrusions at the cell front. These RCP-driven changes in α5β1 trafficking led to acquisition of rapid/random movement on two-dimensional substrates and to a marked increase in fibronectin-dependent migration of tumor cells into three-dimensional matrices. Recycling of α5β1 integrin did not affect its regulation or ability to form adhesive bonds with substrate fibronectin. Instead, α5β1 controlled the association of EGFR1 with RCP to promote the coordinate recycling of these two receptors. This modified signaling downstream of EGFR1 to increase its autophosphorylation and activation of the proinvasive kinase PKB/Akt. We conclude that RCP provides a scaffold that promotes the physical association and coordinate trafficking of α5β1 and EGFR1 and that this drives migration of tumor cells into three-dimensional matrices.

scholarly journals Nonmuscle Myosin IIB Is Involved in the Guidance of Fibroblast Migration

2004 ◽  
Vol 15 (3) ◽  
pp. 982-989 ◽  
Author(s):  
Chun-Min Lo ◽  
Denis B. Buxton ◽  
Gregory C.H. Chua ◽  
Micah Dembo ◽  
Robert S. Adelstein ◽  
...  
Keyword(s):  
Cell Migration ◽  
Large Fraction ◽  
Myosin Ii ◽  
Cell Movement ◽  
Traction Forces ◽  
Migration Patterns ◽  
Fibroblast Migration ◽  
Substrate Rigidity ◽  
Migration Analysis ◽  
Mutant Cells

Although myosin II is known to play an important role in cell migration, little is known about its specific functions. We have addressed the function of one of the isoforms of myosin II, myosin IIB, by analyzing the movement and mechanical characteristics of fibroblasts where this protein has been ablated by gene disruption. Myosin IIB null cells displayed multiple unstable and disorganized protrusions, although they were still able to generate a large fraction of traction forces when cultured on flexible polyacrylamide substrates. However, the traction forces were highly disorganized relative to the direction of cell migration. Analysis of cell migration patterns indicated an increase in speed and decrease in persistence, which were likely responsible for the defects in directional movements as demonstrated with Boyden chambers. In addition, unlike control cells, mutant cells failed to respond to mechanical signals such as compressing forces and changes in substrate rigidity. Immunofluorescence staining indicated that myosin IIB was localized preferentially along stress fibers in the interior region of the cell. Our results suggest that myosin IIB is involved not in propelling but in directing the cell movement, by coordinating protrusive activities and stabilizing the cell polarity.

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