scholarly journals A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Xuan Cao ◽  
Tomonori Kaneko ◽  
Jenny S. Li ◽  
An-Dong Liu ◽  
Courtney Voss ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Rho Gtpases ◽  
Leading Edge ◽  
Small Gtpases ◽  
Pdgf Stimulation ◽  
Epidermal Growth ◽  
Phosphoinositide 3 Kinase ◽  
Directional Cell Migration ◽  
Phosphatase And Tensin Homologue

Abstract Although cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. Here we report that a phosphorylation-mediated molecular switch comprising deleted in liver cancer 1 (DLC1), tensin-3 (TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. On epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) stimulation, TNS3 and PTEN are phosphorylated at specific Thr residues, which trigger the rearrangement of the TNS3–DLC1 and PTEN–PI3K complexes into the TNS3–PI3K and PTEN–DLC1 complexes. Subsequently, the TNS3–PI3K complex translocates to the leading edge of a migrating cell to promote Rac1 activation, whereas PTEN–DLC1 translocates to the posterior for localized RhoA activation. Our work identifies a core signalling mechanism by which an external motility stimulus is coupled to the spatiotemporal activation of Rac1 and RhoA to drive directional cell migration.

scholarly journals Kank regulates RhoA-dependent formation of actin stress fibers and cell migration via 14-3-3 in PI3K–Akt signaling

2008 ◽  
Vol 181 (3) ◽  
pp. 537-549 ◽  
Author(s):  
Naoto Kakinuma ◽  
Badal Chandra Roy ◽  
Yun Zhu ◽  
Yong Wang ◽  
Ryoiti Kiyama
Keyword(s):  
Cell Migration ◽  
Growth Factors ◽  
Growth Factor ◽  
Akt Signaling ◽  
Stress Fibers ◽  
Nih3t3 Cells ◽  
Rhoa Activity ◽  
Epidermal Growth ◽  
Phosphoinositide 3 Kinase ◽  
Actin Stress Fibers

Phosphoinositide-3 kinase (PI3K)/Akt signaling is activated by growth factors such as insulin and epidermal growth factor (EGF) and regulates several functions such as cell cycling, apoptosis, cell growth, and cell migration. Here, we find that Kank is an Akt substrate located downstream of PI3K and a 14-3-3–binding protein. The interaction between Kank and 14-3-3 is regulated by insulin and EGF and is mediated through phosphorylation of Kank by Akt. In NIH3T3 cells expressing Kank, the amount of actin stress fibers is reduced, and the coexpression of 14-3-3 disrupted this effect. Kank also inhibits insulin-induced cell migration via 14-3-3 binding. Furthermore, Kank inhibits insulin and active Akt-dependent activation of RhoA through binding to 14-3-3. Based on these findings, we hypothesize that Kank negatively regulates the formation of actin stress fibers and cell migration through the inhibition of RhoA activity, which is controlled by binding of Kank to 14-3-3 in PI3K–Akt signaling.

scholarly journals Type Iγ phosphatidylinositol phosphate kinase is required for EGF-stimulated directional cell migration

2007 ◽  
Vol 178 (2) ◽  
pp. 297-308 ◽  
Author(s):  
Yue Sun ◽  
Kun Ling ◽  
Matthew P. Wagoner ◽  
Richard A. Anderson
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Egf Receptor ◽  
Adhesion Formation ◽  
Leading Edge ◽  
Directional Migration ◽  
Phosphatidylinositol Phosphate ◽  
Phospholipase Cγ1 ◽  
Directional Cell Migration ◽  
Phosphatidylinositol Phosphate Kinase

Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) modulates a plethora of cytoskeletal interactions that control the dynamics of actin assembly and, ultimately, cell migration. We show that the type Iγ phosphatidylinositol phosphate kinase 661 (PIPKIγ661), an enzyme that generates PI4,5P2, is required for growth factor but not G protein–coupled receptor–stimulated directional migration. By generating PI4,5P2 and regulating talin assembly, PIPKIγ661 modulates nascent adhesion formation at the leading edge to facilitate cell migration. The epidermal growth factor (EGF) receptor directly phosphorylates PIPKIγ661 at tyrosine 634, and this event is required for EGF-induced migration. This phosphorylation regulates the interaction between PIPKIγ661 and phospholipase Cγ1 (PLCγ1, an enzyme previously shown to be involved in the regulation of EGF-stimulated migration). Our results suggest that phosphorylation events regulating specific PIPKIγ661 interactions are required for growth factor–induced migration. These interactions in turn define the spatial and temporal generation of PI4,5P2 and derived messengers required for directional migration.

scholarly journals Epidermal growth factor induction of front–rear polarity and migration in keratinocytes is mediated by integrin-linked kinase and ELMO2

2012 ◽  
Vol 23 (3) ◽  
pp. 492-502 ◽  
Author(s):  
Ernest Ho ◽  
Lina Dagnino
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Egf Receptor ◽  
Leading Edge ◽  
Epidermal Keratinocytes ◽  
Forward Movement ◽  
Integrin Linked Kinase ◽  
Epidermal Growth

Epidermal growth factor (EGF) is a potent chemotactic and mitogenic factor for epidermal keratinocytes, and these properties are central for normal epidermal regeneration after injury. The involvement of mitogen-activated protein kinases as mediators of the proliferative effects of EGF is well established. However, the molecular mechanisms that mediate motogenic responses to this growth factor are not clearly understood. An obligatory step for forward cell migration is the development of front–rear polarity and formation of lamellipodia at the leading edge. We show that stimulation of epidermal keratinocytes with EGF, but not with other growth factors, induces development of front–rear polarity and directional migration through a pathway that requires integrin-linked kinase (ILK), Engulfment and Cell Motility-2 (ELMO2), integrin β1, and Rac1. Furthermore, EGF induction of front–rear polarity and chemotaxis require the tyrosine kinase activity of the EGF receptor and are mediated by complexes containing active RhoG, ELMO2, and ILK. Our findings reveal a novel link between EGF receptor stimulation, ILK-containing complexes, and activation of small Rho GTPases necessary for acquisition of front–rear polarity and forward movement.

scholarly journals A Dual Phosphoinositide-3-Kinase α/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma

2007 ◽  
Vol 67 (17) ◽  
pp. 7960-7965 ◽  
Author(s):  
Qi-Wen Fan ◽  
Christine K. Cheng ◽  
Theodore P. Nicolaides ◽  
Christopher S. Hackett ◽  
Zachary A. Knight ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Mtor Inhibitor ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Phosphoinositide 3 Kinase

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.

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