scholarly journals HGF-induced migration depends on the PI(3,4,5)P3-binding microexon-spliced variant of the Arf6 exchange factor cytohesin-1

2018 ◽  
Vol 218 (1) ◽  
pp. 285-298 ◽  
Author(s):  
Colin D.H. Ratcliffe ◽  
Nadeem Siddiqui ◽  
Paula P. Coelho ◽  
Nancy Laterreur ◽  
Tumini N. Cookey ◽  
...  
Keyword(s):  
Cell Migration ◽  
Leading Edge ◽  
Pleckstrin Homology Domain ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Dependent Cell ◽  
And Migration ◽  
Phosphoinositide Recognition

Differential inclusion or skipping of microexons is an increasingly recognized class of alternative splicing events. However, the functional significance of microexons and their contribution to signaling diversity is poorly understood. The Met receptor tyrosine kinase (RTK) modulates invasive growth and migration in development and cancer. Here, we show that microexon switching in the Arf6 guanine nucleotide exchange factor cytohesin-1 controls Met-dependent cell migration. Cytohesin-1 isoforms, differing by the inclusion of an evolutionarily conserved three-nucleotide microexon in the pleckstrin homology domain, display differential affinity for PI(4,5)P2 (triglycine) and PI(3,4,5)P3 (diglycine). We show that selective phosphoinositide recognition by cytohesin-1 isoforms promotes distinct subcellular localizations, whereby the triglycine isoform localizes to the plasma membrane and the diglycine to the leading edge. These data highlight microexon skipping as a mechanism to spatially restrict signaling and provide a mechanistic link between RTK-initiated phosphoinositide microdomains and Arf6 during signal transduction and cancer cell migration.

scholarly journals Guanine Nucleotide Exchange Factor-H1 Regulates Cell Migration via Localized Activation of RhoA at the Leading Edge

2009 ◽  
Vol 20 (18) ◽  
pp. 4070-4082 ◽  
Author(s):  
Perihan Nalbant ◽  
Yuan-Chen Chang ◽  
Jörg Birkenfeld ◽  
Zee-Fen Chang ◽  
Gary M. Bokoch
Keyword(s):  
Cell Migration ◽  
Focal Adhesion ◽  
Leading Edge ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Rhoa Activity ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

Cell migration involves the cooperative reorganization of the actin and microtubule cytoskeletons, as well as the turnover of cell–substrate adhesions, under the control of Rho family GTPases. RhoA is activated at the leading edge of motile cells by unknown mechanisms to control actin stress fiber assembly, contractility, and focal adhesion dynamics. The microtubule-associated guanine nucleotide exchange factor (GEF)-H1 activates RhoA when released from microtubules to initiate a RhoA/Rho kinase/myosin light chain signaling pathway that regulates cellular contractility. However, the contributions of activated GEF-H1 to coordination of cytoskeletal dynamics during cell migration are unknown. We show that small interfering RNA-induced GEF-H1 depletion leads to decreased HeLa cell directional migration due to the loss of the Rho exchange activity of GEF-H1. Analysis of RhoA activity by using a live cell biosensor revealed that GEF-H1 controls localized activation of RhoA at the leading edge. The loss of GEF-H1 is associated with altered leading edge actin dynamics, as well as increased focal adhesion lifetimes. Tyrosine phosphorylation of focal adhesion kinase and paxillin at residues critical for the regulation of focal adhesion dynamics was diminished in the absence of GEF-H1/RhoA signaling. This study establishes GEF-H1 as a critical organizer of key structural and signaling components of cell migration through the localized regulation of RhoA activity at the cell leading edge.

scholarly journals DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4451-4461 ◽  
Author(s):  
Yosuke Harada ◽  
Yoshihiko Tanaka ◽  
Masao Terasawa ◽  
Markus Pieczyk ◽  
Katsuyoshi Habiro ◽  
...  
Keyword(s):  
Leading Edge ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Subcapsular Sinus ◽  
Dendritic Cell Migration ◽  
And Migration

Abstract To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially.

scholarly journals ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration

2008 ◽  
Vol 181 (2) ◽  
pp. 351-365 ◽  
Author(s):  
Junji Yamauchi ◽  
Yuki Miyamoto ◽  
Jonah R. Chan ◽  
Akito Tanoue
Keyword(s):  
Cell Migration ◽  
Schwann Cell ◽  
Rho Gtpase ◽  
Morphological Changes ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Schwann Cell Migration ◽  
Subsequent Activation

The cellular events that precede myelination in the peripheral nervous system require rapid and dynamic morphological changes in the Schwann cell. These events are thought to be mainly controlled by axonal signals. But how signals on the axons are coordinately organized and transduced to promote proliferation, migration, radial sorting, and myelination is unknown. We describe that the axonal signal neuregulin-1 (NRG1) controls Schwann cell migration via activation of the atypical Dock180-related guanine nucleotide exchange factor (GEF) Dock7 and subsequent activation of the Rho guanine triphosphatases (GTPases) Rac1 and Cdc42 and the downstream c-Jun N-terminal kinase. We show that the NRG1 receptor ErbB2 directly binds and activates Dock7 by phosphorylating Tyr-1118. Dock7 knockdown, or expression of Dock7 harboring the Tyr-1118–to–Phe mutation in Schwann cells, attenuates the effects of NRG1. Thus, Dock7 functions as an intracellular substrate for ErbB2 to promote Schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of Rho GTPase-GEFs of the Dock180 family.

Human p63RhoGEF, a novel RhoA-specific guanine nucleotide exchange factor, is localized in cardiac sarcomere

2002 ◽  
Vol 115 (3) ◽  
pp. 629-640 ◽  
Author(s):  
Michel Souchet ◽  
Elodie Portales-Casamar ◽  
David Mazurais ◽  
Susanne Schmidt ◽  
Isabelle Léger ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factor ◽  
Small Gtpases ◽  
Fiber Formation ◽  
Pleckstrin Homology Domain ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Intact Cells ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

The Rho small GTPases are crucial proteins involved in regulation of signal transduction cascades from extracellular stimuli to cell nucleus and cytoskeleton. It has been reported that these GTPases are directly associated with cardiovascular disorders. In this context, we have searched for novel modulators of Rho GTPases, and here we describe p63RhoGEF a new Db1-like guanine nucleotide exchange factor (GEF). P63RhoGEF encodes a 63 kDa protein containing a Db1 homology domain in tandem with a pleckstrin homology domain and is most closely related to the second Rho GEF domain of Trio. Northern blot and in situ analysis have shown that p63RhoGEF is mainly expressed in heart and brain. In vitro guanine nucleotide exchange assays have shown that p63RhoGEF specifically acts on RhoA. Accordingly, p63RhoGEF expression induces RhoA-dependent stress fiber formation in fibroblasts and in H9C2 cardiac myoblasts. Moreover, we show that p63RhoGEF activation of RhoA in intact cells is dependent on the presence of the PH domain. Using a specific anti-p63RhoGEF antibody, we have detected the p63RhoGEF protein by immunocytochemistry in human heart and brain tissue sections. Confocal microscopy shows that p63RhoGEF is located in the sarcomeric I-band mainly constituted of cardiac sarcomeric actin. Together, these results show that p63RhoGEF is a RhoA-specific GEF that may play a key role in actin cytoskeleton reorganization in different tissues, especially in heart cellular morphology.

Trio amino-terminal guanine nucleotide exchange factor domain expression promotes actin cytoskeleton reorganization, cell migration and anchorage-independent cell growth

1999 ◽  
Vol 112 (12) ◽  
pp. 1825-1834 ◽  
Author(s):  
K. Seipel ◽  
Q.G. Medley ◽  
N.L. Kedersha ◽  
X.A. Zhang ◽  
S.P. O'Brien ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Growth ◽  
Actin Cytoskeleton ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Amino Terminal ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

Rho family GTPases regulate diverse cellular processes, including extracellular signal-mediated actin cytoskeleton reorganization and cell growth. The functions of GTPases are positively regulated by guanine nucleotide exchange factors, which promote the exchange of GDP for GTP. Trio is a complex protein possessing two guanine nucleotide exchange factor domains, each with adjacent pleckstrin homology and SH3 domains, a protein serine/threonine kinase domain with an adjacent immunoglobulin-like domain and multiple spectrin-like domains. To assess the functional role of the two Trio guanine nucleotide exchange factor domains, NIH 3T3 cell lines stably expressing the individual guanine nucleotide exchange factor domains were established and characterized. Expression of the amino-terminal guanine nucleotide exchange factor domain results in prominent membrane ruffling, whereas cells expressing the carboxy-terminal guanine nucleotide exchange factor domain have lamellae that terminate in miniruffles. Moreover, cells expressing the amino-terminal guanine nucleotide exchange factor domain display more rapid cell spreading, haptotactic cell migration and anchorage-independent growth, suggesting that Trio regulates both cell motility and cell growth. Expression of full-length Trio in COS cells also alters actin cytoskeleton organization, as well as the distribution of focal contact sites. These findings support a role for Trio as a multifunctional protein that integrates and amplifies signals involved in coordinating actin remodeling, which is necessary for cell migration and growth.

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