Results 1 - 10 of 200

Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell Res

by Robert N. Jorissen, Francesca Walker, C Norm, Thomas P. J. Garrett, Colin W. Ward, Antony W. Burgessa - J. Cell Biol , 2003
"... The epidermal growth factor (EGF) receptor (EGFR) is one of four homologous transmembrane proteins that mediate the actions of a family of growth factors including EGF, transforming growth factor-, and the neuregulins. We review the structure and function of the EGFR, from ligand binding to the init ..."
Abstract - Cited by 162 (0 self) - Add to MetaCart
The epidermal growth factor (EGF) receptor (EGFR) is one of four homologous transmembrane proteins that mediate the actions of a family of growth factors including EGF, transforming growth factor-, and the neuregulins. We review the structure and function of the EGFR, from ligand binding to the initiation of intracellular signalling pathways that lead to changes in the biochemical state of the cell. The recent crystal structures of different domains from several members of the EGFR family have challenged our concepts of these processes. © 2003 Elsevier Science (USA). All rights reserved.

Cell motility: Can Rho GTPases and microtubules point the way

by Torsten Wittmann, Clare M. Waterman-storer - J. Cell Sci. 114(Pt , 2001
"... Migrating cells display a characteristic polarization of the actin cytoskeleton. Actin filaments polymerise in the protruding front of the cell whereas actin filament bundles contract in the cell body, which results in retraction of the cell’s rear. The dynamic organization of the actin cytoskeleton ..."
Abstract - Cited by 62 (6 self) - Add to MetaCart
Migrating cells display a characteristic polarization of the actin cytoskeleton. Actin filaments polymerise in the protruding front of the cell whereas actin filament bundles contract in the cell body, which results in retraction of the cell’s rear. The dynamic organization of the actin cytoskeleton provides the force for cell motility and is regulated by small GTPases of the Rho family, in particular Rac1, RhoA and Cdc42. Although the microtubule cytoskeleton is also polarized in a migrating cell, and microtubules are essential for the directed migration of many cell types, their role in cell motility is not well understood at a molecular level. Here, we discuss the potential molecular mechanisms for interplay of microtubules, actin and Rho GTPase signalling in cell polarization and motility. Recent evidence suggests that microtubules locally modulate the activity of Rho GTPases and, conversely, Rho GTPases might be responsible for the initial polarization of the microtubule cytoskeleton. Thus, microtubules might be part of a positive feedback mechanism that maintains the stable polarization of a directionally migrating cell.
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A role for p21-activated kinase in endothelial cell migration

by William B. Kiosses, R. Hugh Daniels, Carol Otey, Gary M. Bokoch, Martin Alex, Er Schwartz - J. Cell , 1999
"... Abstract. The serine/threonine p21-activated kinase (PAK) is an effector for Rac and Cdc42, but its role in regulating cytoskeletal organization has been controversial. To address this issue, we investigated the role of PAK in migration of microvascular endothelial cells. We found that a dominant ne ..."
Abstract - Cited by 45 (3 self) - Add to MetaCart
Abstract. The serine/threonine p21-activated kinase (PAK) is an effector for Rac and Cdc42, but its role in regulating cytoskeletal organization has been controversial. To address this issue, we investigated the role of PAK in migration of microvascular endothelial cells. We found that a dominant negative (DN) mutant of PAK significantly inhibited cell migration and increased stress fibers and focal adhesions. The DN effect mapped to the most NH 2-terminal proline-rich SH3binding sequence. Observation of a green fluorescent protein-tagged �-actinin construct in living cells revealed that the DN construct had no effect on membrane ruffling, but dramatically inhibited stress fiber and focal contact motility and turnover. Constitutively active PAK inhibited migration equally well and also
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p120 catenin regulates the actin cytoskeleton via rho family GTPases

by Nicole K. Noren, Betty P. Liu, Keith Burridge, Bertolt Kreft - J. Cell , 2000
"... Abstract. Cadherins are calcium-dependent adhesion molecules responsible for the establishment of tight cell–cell contacts. p120 catenin (p120ctn) binds to the cytoplasmic domain of cadherins in the juxtamembrane region, which has been implicated in regulating cell motility. It has previously been s ..."
Abstract - Cited by 42 (0 self) - Add to MetaCart
Abstract. Cadherins are calcium-dependent adhesion molecules responsible for the establishment of tight cell–cell contacts. p120 catenin (p120ctn) binds to the cytoplasmic domain of cadherins in the juxtamembrane region, which has been implicated in regulating cell motility. It has previously been shown that overexpression of p120ctn induces a dendritic morphology in fibroblasts
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Molecular mechanisms of epithelial morphogenesis.

by Frieder Schöck , Norbert Perrimon - Annu Rev Cell Dev Biol , 2002
"... Abstract Epithelial morphogenesis comprises the various processes by which epithelia contribute to organ formation and body shape. These complex and diverse events play a central role in animal development and regeneration. Recently, the characterization of some of the molecular mechanisms involved ..."
Abstract - Cited by 40 (0 self) - Add to MetaCart
Abstract Epithelial morphogenesis comprises the various processes by which epithelia contribute to organ formation and body shape. These complex and diverse events play a central role in animal development and regeneration. Recently, the characterization of some of the molecular mechanisms involved in epithelial morphogenesis has provided an abundance of new information on the role and regulation of the cytoskeleton, cell-cell adhesion, and cell-matrix adhesion in these processes. In this review, we discuss our current understanding of the molecular mechanisms driving cell shape changes, cell intercalation, fusion of epithelia, ingression, egression, and cell migration. Our discussion is mostly focused on results from Drosophila and mammalian tissue culture but also draws on the insights gained from other organisms.

Localized RhoA activation as a requirement for the induction of membrane ruffling

by Kazuo Kurokawa, Michiyuki Matsuda - Mol. Biol. Cell , 2005
"... We examined the spatio-temporal activity of RhoA in migrating cells and growth factorstimulated cells by using probes based on the principle of fluorescence resonance energy transfer. In HeLa cells migrating at a low cell density, RhoA was activated both at the contractile tail and at the leading ed ..."
Abstract - Cited by 38 (1 self) - Add to MetaCart
We examined the spatio-temporal activity of RhoA in migrating cells and growth factorstimulated cells by using probes based on the principle of fluorescence resonance energy transfer. In HeLa cells migrating at a low cell density, RhoA was activated both at the contractile tail and at the leading edge. However, RhoA was activated only at the leading edge in MDCK cells migrating as a monolayer sheet. In growth factor-stimulated Cos1 and NIH3T3 cells, the activity of RhoA was greatly decreased at the plasma membrane, but remained high at the membrane ruffles in nascent lamellipodia. These observations are in agreement with the proposed role played by RhoA in stress fiber formation, but they also implicated RhoA in the regulation of membrane ruffling, the induction of which is a typical phenotype of activated Rac. In agreement with this view, dominant negative RhoA was found to inhibit membrane ruffling induced by active Rac. Furthermore, we found that Cdc42 activity was also required for high RhoA activity in membrane ruffles. Finally, we found that mDia1, but not ROCK, was stably associated with membrane ruffles. In conclusion, these results suggested that RhoA cooperates with Rac1 and Cdc42 to induce membrane ruffles via the recruitment of mDia. 2
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A, Roberts J: p27Kip1 modulates cell migration through the regulation of RhoA activation

by Arnaud Besson, Mark Gurian-west, Anja Schmidt, Alan Hall, James M. Roberts - Genes Dev
"... The tumor suppressor p27 Kip1 is an inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes and plays a crucial role in cell cycle regulation. However, p27 Kip1 also has cell cycle-independent functions. Indeed, we find that p27 Kip1 regulates cell migration, as p27 Kip1-null fibroblasts exhibit ..."
Abstract - Cited by 36 (5 self) - Add to MetaCart
The tumor suppressor p27 Kip1 is an inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes and plays a crucial role in cell cycle regulation. However, p27 Kip1 also has cell cycle-independent functions. Indeed, we find that p27 Kip1 regulates cell migration, as p27 Kip1-null fibroblasts exhibit a dramatic decrease in motility compared with wild-type cells. The regulation of motility by p27 Kip1 is independent of its cell-cycle regulatory functions, as re-expression of both wild-type p27 Kip1 and a mutant p27 Kip1 (p27CK − ) that cannot bind to cyclins and CDKs rescues migration of p27 −/ − cells. p27 −/ − cells have increased numbers of actin stress fibers and focal adhesions. This is reminiscent of cells in which the Rho pathway is activated. Indeed, active RhoA levels were increased in cells lacking p27 Kip1. Moreover, inhibition of ROCK, a downstream effector of Rho, was able to rescue the migration defect of p27 −/ − cells in response to growth factors. Finally, we found that p27 Kip1 binds to RhoA, thereby inhibiting RhoA activation by interfering with the interaction between RhoA and its activators, the guanine–nucleotide exchange factors (GEFs). Together, the data suggest a novel role for p27 Kip1 in regulating cell migration via modulation of the Rho pathway. [Keywords: p27 Kip1; Rho; migration; actin stress fibers; Ras; ROCK] Supplemental material is available at
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Amoeboid leukocyte crawling through extracellular matrix: lessons from the Dictyostelium paradigm of cell movement

by Peter Friedl, Stefan Borgmann - J. Leukocyte Biol , 2001
"... Abstract: Cell movement within three-dimen-sional tissues is a cycling multistep process that requires the integration of complex biochemical and biophysical cell functions. Different cells solve this challenge differently, which leads to differ-ences in migration strategies. Migration principles es ..."
Abstract - Cited by 34 (1 self) - Add to MetaCart
Abstract: Cell movement within three-dimen-sional tissues is a cycling multistep process that requires the integration of complex biochemical and biophysical cell functions. Different cells solve this challenge differently, which leads to differ-ences in migration strategies. Migration principles established for leukocytes share many characteris-tics with those described for ameba of the lower eukaryote Dictyostelium discoideum. The hall-marks of amoeboid movement include a simple polarized shape, dynamic pseudopod protrusion and retraction, flexible oscillatory shape changes, and rapid low-affinity crawling. Amoeboid crawling includes haptokinetic adhesion-dependent as well as biophysical migration mechanisms on or within many structurally and functionally different sub-strates. We describe central aspects of amoeboid movement in leukocytes and the implications for leukocyte crawling and positioning strategies within interstitial tissues. J. Leukoc. Biol. 70: 491–509; 2001. Key Words: T lymphocytes z collagen matrix z cytoskeletal dy-namics z migration strategies
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Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases

by Elisabeth A. Cox, Sarita K. Sastry, Anna Huttenlocher - Mol. Biol. Cell , 2001
"... Integrin-mediated adhesion is a critical regulator of cell migration. Here we demonstrate that integrin-mediated adhesion to high fibronectin concentrations induces a stop signal for cell migration by inhibiting cell polarization and protrusion. On fibronectin, the stop signal is generated through � ..."
Abstract - Cited by 32 (3 self) - Add to MetaCart
Integrin-mediated adhesion is a critical regulator of cell migration. Here we demonstrate that integrin-mediated adhesion to high fibronectin concentrations induces a stop signal for cell migration by inhibiting cell polarization and protrusion. On fibronectin, the stop signal is generated through �5�1 integrin-mediated signaling to the Rho family of GTPases. Specifically, Cdc42 and Rac1 activation exhibits a biphasic dependence on fibronectin concentration that parallels optimum cell polarization and protrusion. In contrast, RhoA activity increases with increasing substratum concentration. We find that cross talk between Cdc42 and Rac1 is required for substratum-stimulated protrusion, whereas RhoA activity is inhibitory. We also show that Cdc42 activity is inhibited by Rac1 activation, suggesting that Rac1 activity may down-regulate Cdc42 activity and promote the formation of stabilized rather than transient protrusion. Furthermore, expression of RhoA down-regulates Cdc42 and Rac1 activity, providing a mechanism whereby RhoA may inhibit cell polarization and protrusion. These findings implicate adhesion-dependent signaling as a mechanism to stop cell migration by regulating cell polarity and protrusion via the Rho family of GTPases.
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Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity

by Karni Schlessinger, Edward J. Mcmanus, Alan Hall - J Cell Biol
"... Scratch-induced disruption of cultured monolayers induces polarity in front row cells that can be visualized by spatially localized polymerization of actin at the front of the cell and reorientation of the centrosome/Golgi to face the leading edge. We previously reported that centrosomal reorientati ..."
Abstract - Cited by 29 (0 self) - Add to MetaCart
Scratch-induced disruption of cultured monolayers induces polarity in front row cells that can be visualized by spatially localized polymerization of actin at the front of the cell and reorientation of the centrosome/Golgi to face the leading edge. We previously reported that centrosomal reorientation and microtubule polarization depend on a Cdc42-regulated signal transduction pathway involving activation of the Par6/ aPKC complex followed by inhibition of GSK-3β and accumulation of the adenomatous polyposis coli (APC)
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