Integrin regulation of cell signalling and motility

2004 ◽  
Vol 32 (3) ◽  
pp. 443-446 ◽  
Author(s):  
R.L. Juliano ◽  
P. Reddig ◽  
S. Alahari ◽  
M. Edin ◽  
A. Howe ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Kinase ◽  
Cell Signalling ◽  
Mitogen Activated Protein Kinase ◽  
Integrin Subunit ◽  
Actin Organization ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
And Migration ◽  
Integrin Regulation

Integrins clearly play a key role in regulating both mitogenic signalling and cell migration. Thus integrins modulate the efficiency of the Erk (extracellular-signal-regulated kinase)/MAP kinase (mitogen-activated protein kinase) pathway, acting at several distinct levels. We have shown that both cAMP-dependent protein kinase and PAKs (p21-activated kinases) play a role in integrin regulation of the Erk pathway, acting primarily at the level of Raf-1. Integrins and PAKs also play a role in the control of cell migration. Thus we have discovered a novel protein that links the α5β1 integrin to migration controlled by Rho-family GTPases. This protein, termed Nischarin, is a large cytosolic macromolecule that is not related to well-known protein families. The N-terminus of Nischarin interacts with a short segment of the cytoplasmic domain of the α5 integrin subunit. Overexpression of Nischarin alters actin organization and inhibits Rac-driven cell migration and tumour cell invasion. Use of effector domain mutants of Rac suggest that Nischarin acts downstream of Rac, probably at the level of PAK-family kinases. These studies emphasize the intricate connection between integrins and Rho-family GTPases and their effectors in controlling both mitogenesis and migration.

Integrin regulation of membrane domain trafficking and Rac targeting

2005 ◽  
Vol 33 (4) ◽  
pp. 609-613 ◽  
Author(s):  
A. Grande-García ◽  
A. Echarri ◽  
M.A. Del Pozo
Keyword(s):  
Cell Growth ◽  
Binding Sites ◽  
Cell Cycle Progression ◽  
Membrane Microdomains ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
And Migration ◽  
Integrin Regulation

Integrins are crucial regulators of essential cellular processes such as gene expression, cell proliferation and migration. Alteration of these processes is central to tumourigenesis. Integrin signals mediate anchorage dependence of cell growth, while growth of cancer cells is anchorage-independent. Integrins critically regulate Rho family GTPases, that are also involved in cell-cycle progression and oncogenesis. In addition to their effect on GTP loading, integrins independently control the translocation of GTP-bound Rac to the plasma membrane. This step is essential for Rac binding to effectors. Integrins increase membrane affinity for Rac, leading to RhoGDI dissociation and effector coupling locally, in the vicinity of activated/bound integrins. Integrin-regulated Rac binding sites are within CEMMs (cholesterol-enriched membrane microdomains). Integrins control Rac signalling by preventing the internalization of its binding sites in CEMMs. Integrin regulation of signalling pathways initiated in CEMMs may be important for the spatial control of cell migration and anchorage dependence of cell growth.

scholarly journals Rho Family GTPases Regulate p38 Mitogen-activated Protein Kinase through the Downstream Mediator Pak1

1995 ◽  
Vol 270 (41) ◽  
pp. 23934-23936 ◽  
Author(s):  
Shengjia Zhang ◽  
Jiahuai Han ◽  
Mary Ann Sells ◽  
Jonathan Chernoff ◽  
Ulla G. Knaus ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Rho Family Gtpases ◽  
Mitogen Activated Protein ◽  
Rho Family ◽  
Downstream Mediator

Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4142-4151 ◽  
Author(s):  
Marcin Majka ◽  
Anna Janowska-Wieczorek ◽  
Janina Ratajczak ◽  
M. Anna Kowalska ◽  
Gaston Vilaire ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Phosphatidyl Inositol ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Proliferative Effect ◽  
Normal Human ◽  
And Migration ◽  
Induced Apoptosis

Abstract The role of the chemokine binding stromal-derived factor 1 (SDF-1) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin (TPO) have not been determined. In this study it was found that SDF-1, unlike TPO, does not stimulate αIIbβ3+ cell proliferation or differentiation or have an antiapoptotic effect. However, it does induce chemotaxis, trans-Matrigel migration, and secretion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO increase the adhesion of αIIbβ3+ cells to fibrinogen and vitronectin. Investigating the intracellular signaling pathways induced by SDF-1 and TPO revealed some overlapping patterns of protein phosphorylation/activation (mitogen-activated protein kinase [MAPK] p42/44, MAPK p38, and AKT [protein kinase B]) and some that were distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF-κB). It was also found that though inhibition of phosphatidyl-inositol 3-kinase (PI-3K) by LY294002 in αIIbβ3+ cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF, the inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no effect on the survival, proliferation, and migration of these cells. Hence, it is suggested that the proliferative effect of TPO is more related to activation of the JAK-STAT pathway (unique to TPO), and the PI-3K–AKT axis is differentially involved in TPO- and SDF-1–dependent signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of apoptosis, TPO- and SDF-1–regulated adhesion to fibrinogen and vitronectin, and SDF-1–mediated migration. This study expands the understanding of the role of SDF-1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses.

scholarly journals Specific Activation of Mitogen-activated Protein Kinase by Transforming Growth Factor-β Receptors in Lipid Rafts Is Required for Epithelial Cell Plasticity

2009 ◽  
Vol 20 (3) ◽  
pp. 1020-1029 ◽  
Author(s):  
Wei Zuo ◽  
Ye-Guang Chen
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Protein Kinase ◽  
Lipid Rafts ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Coated Pits ◽  
Mapk Activation ◽  
Mitogen Activated Protein

Transforming growth factor (TGF)-β regulates a spectrum of cellular events, including cell proliferation, differentiation, and migration. In addition to the canonical Smad pathway, TGF-β can also activate mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and small GTPases in a cell-specific manner. Here, we report that cholesterol depletion interfered with TGF-β–induced epithelial-mesenchymal transition (EMT) and cell migration. This interference is due to impaired activation of MAPK mediated by cholesterol-rich lipid rafts. Cholesterol-depleting agents specifically inhibited TGF-β–induced activation of extracellular signal-regulated kinase (ERK) and p38, but not Smad2/3 or Akt. Activation of ERK or p38 is required for both TGF-β–induced EMT and cell migration, whereas PI3K/Akt is necessary only for TGF-β–promoted cell migration but not for EMT. Although receptor heterocomplexes could be formed in both lipid raft and nonraft membrane compartments in response to TGF-β, receptor localization in lipid rafts, but not in clathrin-coated pits, is important for TGF-β–induced MAPK activation. Requirement of lipid rafts for MAPK activation was further confirmed by specific targeting of the intracellular domain of TGF-β type I receptor to different membrane locations. Together, our findings establish a novel link between cholesterol and EMT and cell migration, that is, cholesterol-rich lipid rafts are required for TGF-β–mediated MAPK activation, an event necessary for TGF-β–directed epithelial plasticity.

scholarly journals Overexpression of a Neural-specific Rho Family GTPase, cRac1B, Selectively Induces Enhanced Neuritogenesis and Neurite Branching in Primary Neurons

1998 ◽  
Vol 142 (3) ◽  
pp. 815-825 ◽  
Author(s):  
Chiara Albertinazzi ◽  
Daniela Gilardelli ◽  
Simona Paris ◽  
Renato Longhi ◽  
Ivan de Curtis
Keyword(s):  
Neural Development ◽  
Neuronal Morphology ◽  
Primary Neurons ◽  
Actin Organization ◽  
Inactive Form ◽  
Rho Family Gtpases ◽  
Neurite Formation ◽  
New Gene ◽  
Rho Family

Rho family GTPases have been implicated in cytoskeletal reorganization during neuritogenesis. We have recently identified a new gene of this family, cRac1B, specifically expressed in the chicken developing nervous system. This GTPase was overexpressed in primary neurons to study the role of cRac1B in the development of the neuronal phenotype. Overexpression of cRac1B induced an increment in the number of neurites per neuron, and dramatically increased neurite branching, whereas overexpression of the highly related and ubiquitous cRac1A GTPase did not evidently affect neuronal morphology. Furthermore, expression of an inactive form of cRac1B strikingly inhibited neurite formation. The specificity of cRac1B action observed in neurons was not observed in fibroblasts, where both GTPases produced similar effects on cell morphology and actin organization, indicating the existence of a cell type-dependent specificity of cRac1B function. Molecular dissection of cRac1B function by analysis of the effects of chimeric cRac1A/cRac1B proteins showed that the COOH-terminal portion of cRac1B is essential to induce increased neuritogenesis and neurite branching. Considering the distinctive regulation of cRac1B expression during neural development, our data strongly support an important role of cRac1B during neuritogenesis, and they uncover new mechanisms underlying the functional specificity of distinct Rho family GTPases.

AMPK, MAPK and Bax in the heart: some questions answered

2008 ◽  
Vol 412 (2) ◽  
pp. e15-e16 ◽  
Author(s):  
Vilmante Borutaite
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Wide Field ◽  
Biochemical Journal ◽  
Mitogen Activated Protein ◽  
Isolated Cardiac Myocytes ◽  
And Migration ◽  
Induced Apoptosis ◽  
Amp Activated Protein Kinase ◽  
Rapid Activation

The question of how Bax is activated during apoptosis to perform its role in permeabilization of mitochondrial membranes is intriguing for investigators in the wide field of cell death research. In their paper published in the Biochemical Journal in 2006, Capano and Crompton presented their discovery that simulated ischaemia causes rapid activation of AMPK (AMP-activated protein kinase) which phosphorylates and activates p38 MAPK (mitogen-activated protein kinase) leading to Bax activation and translocation to mitochondria in isolated cardiac myocytes. This was the first report on the molecular mechanism of Bax activation and migration during ischaemia-induced apoptosis in cardiomyocytes.

Regulation of cell migration by the integrin beta subunit ectodomain

1996 ◽  
Vol 109 (6) ◽  
pp. 1615-1622 ◽  
Author(s):  
E.J. Filardo ◽  
S.L. Deming ◽  
D.A. Cheresh
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Cell Spreading ◽  
Biological Properties ◽  
Beta Subunit ◽  
Integrin Subunit ◽  
Cytokine Activation ◽  
Factor Alpha ◽  
And Migration ◽  
Alpha V Beta 3

CS-1 melanoma cells transfected with cDNAs encoding either the beta 3 or beta 5 integrin subunit protein express alpha v beta 3 or alpha v beta 5, respectively, enabling them to adhere to vitronectin yet only alpha v beta 3 promotes cell spreading and migration on this substrate. Following exposure to insulin or insulin-like growth factor, alpha v beta 5-expressing CS-1 cells gain the ability to migrate on vitronectin. To identify structural regions in beta 3 or beta 5 that account for these distinct biological properties, CS-1 cells were transfected with one of two chimeric beta subunit proteins, in which the ecto- and cytoplasmic domains of beta 3 and beta 5 were exchanged (termed alpha v beta 3/5 or alpha v beta 5/3). Surprisingly, alpha v beta 3/5 expressing cells spread and migrate on vitronectin while cells expressing alpha v beta 5/3 do not unless they are exposed to cytokine. These findings suggest that the distinct migratory properties mediated by integrins alpha v beta 3 and alpha v beta 5 and their response to cytokine activation is determined by a sequence(s) within the ectodomain of the integrin beta subunit.

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