scholarly journals Mena binds α5 integrin directly and modulates α5β1 function

2012 ◽  
Vol 198 (4) ◽  
pp. 657-676 ◽  
Author(s):  
Stephanie L. Gupton ◽  
Daisy Riquelme ◽  
Shannon K. Hughes-Alford ◽  
Jenny Tadros ◽  
Shireen S. Rudina ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Growth Factor Receptor ◽  
Focal Adhesions ◽  
Fibronectin Receptor ◽  
Focal Adhesion Proteins ◽  
Carboxy Terminal ◽  
Bidirectional Interactions ◽  
Dependent Processes ◽  
Α5β1 Integrin

Mena is an Ena/VASP family actin regulator with roles in cell migration, chemotaxis, cell–cell adhesion, tumor cell invasion, and metastasis. Although enriched in focal adhesions, Mena has no established function within these structures. We find that Mena forms an adhesion-regulated complex with α5β1 integrin, a fibronectin receptor involved in cell adhesion, motility, fibronectin fibrillogenesis, signaling, and growth factor receptor trafficking. Mena bound directly to the carboxy-terminal portion of the α5 cytoplasmic tail via a 91-residue region containing 13 five-residue “LERER” repeats. In fibroblasts, the Mena–α5 complex was required for “outside-in” α5β1 functions, including normal phosphorylation of FAK and paxillin and formation of fibrillar adhesions. It also supported fibrillogenesis and cell spreading and controlled cell migration speed. Thus, fibroblasts require Mena for multiple α5β1-dependent processes involving bidirectional interactions between the extracellular matrix and cytoplasmic focal adhesion proteins.

scholarly journals N-Cadherin and Keratinocyte Growth Factor Receptor Mediate the Functional Interplay between Ki-RASG12V and p53V143A in Promoting Pancreatic Cell Migration, Invasion, and Tissue Architecture Disruption

2006 ◽  
Vol 26 (11) ◽  
pp. 4185-4200 ◽  
Author(s):  
Therese B. Deramaudt ◽  
Munenori Takaoka ◽  
Rabi Upadhyay ◽  
Mark J. Bowser ◽  
Jess Porter ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Tumor Suppressor ◽  
Keratinocyte Growth Factor ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Pancreatic Cell ◽  
Ductal Cells ◽  
Tumor Suppressor Gene Inactivation

ABSTRACT The genetic basis of pancreatic ductal adenocarcinoma, which constitutes the most common type of pancreatic malignancy, involves the sequential activation of oncogenes and inactivation of tumor suppressor genes. Among the pivotal genetic alterations are Ki-RAS oncogene activation and p53 tumor suppressor gene inactivation. We explain that the combination of these genetic events facilitates pancreatic carcinogenesis as revealed in novel three-dimensional cell (spheroid cyst) culture and in vivo subcutaneous and orthotopic xenotransplantation models. N-cadherin, a member of the classic cadherins important in the regulation of cell-cell adhesion, is induced in the presence of Ki-RAS mutation but subsequently downregulated with the acquisition of p53 mutation as revealed by gene microarrays and corroborated by reverse transcription-PCR and Western blotting. N-cadherin modulates the capacity of pancreatic ductal cells to migrate and invade, in part via complex formation with keratinocyte growth factor receptor and neural cell adhesion molecule and in part via interaction with p120-catenin. However, modulation of these complexes by Ki-RAS and p53 leads to enhanced cell migration and invasion. This preferentially induces the downstream effector AKT over mitogen-activated protein kinase to execute changes in cellular behavior. Thus, we are able to define molecules that in part are directly affected by Ki-RAS and p53 during pancreatic ductal carcinogenesis, and this provides a platform for potential new molecularly based therapeutic interventions.

PECAM-1 isoform-specific regulation of kidney endothelial cell migration and capillary morphogenesis

2007 ◽  
Vol 292 (6) ◽  
pp. C2070-C2083 ◽  
Author(s):  
Shuji Kondo ◽  
Elizabeth A. Scheef ◽  
Nader Sheibani ◽  
Christine M. Sorenson
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Vascular Development ◽  
Focal Adhesions ◽  
Endothelial Cell Migration ◽  
Extracellular Matrix Protein ◽  
Wild Type ◽  
Renal Vasculature ◽  
Capillary Morphogenesis

Platelet endothelial cell adhesion molecule-1 (PECAM-1) has been implicated in angiogenesis through its involvement in endothelial cell-cell and cell-matrix interactions and signal transduction. Recent studies indicate that the cytoplasmic domain of PECAM-1 plays an important role in its cell adhesive and signaling properties. However, the role PECAM-1 isoforms play during angiogenic events such as cell adhesion and migration requires further delineation. To gain insight into the role PECAM-1 plays during vascular development and angiogenesis, we examined the expression pattern of PECAM-1 isoforms during kidney vascularization. We show that multiple isoforms of PECAM-1 are expressed during renal vascular development with different frequencies. The PECAM-1 that lacks exons 14 and 15 (Δ14&15) was the predominant isoform detected in the renal vasculature. To further study PECAM-1 isoform-specific functions we isolated kidney endothelial cells (EC) from wild-type and PECAM-1-deficient (PECAM-1−/−) mice with B4-lectin-coated magnetic beads. PECAM-1−/− kidney EC showed reduced migration, inability to undergo capillary morphogenesis in Matrigel, dense peripheral focal adhesions, and peripheral cortical actin distribution compared with wild-type cells. PECAM-1−/− kidney EC secreted increased amounts of fibronectin and decreased amounts of tenascin-C and thrombospondin-1. Reexpression of Δ14&15, but not full-length, PECAM-1 in PECAM-1−/− kidney EC restored cell migration and capillary morphogenesis defects. Thus PECAM-1 may regulate the adhesive and migratory properties of kidney EC in an isoform-specific fashion through modulation of integrin activity and extracellular matrix protein expression. Our results indicate that regulated expression of specific PECAM-1 isoforms may enable EC to accommodate the different stages of angiogenesis.

scholarly journals Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin.

1989 ◽  
Vol 109 (3) ◽  
pp. 1321-1330 ◽  
Author(s):  
E A Wayner ◽  
A Garcia-Pardo ◽  
M J Humphries ◽  
J A McDonald ◽  
W G Carter
Keyword(s):  
Cell Adhesion ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Plasma Fibronectin ◽  
Fibronectin Receptor ◽  
Lymphocyte Adhesion ◽  
Receptor Alpha ◽  
Tryptic Fragment ◽  
Carboxy Terminal ◽  
Adhesion Site

Using mAb technology (Wayner, E. A., W. G. Carter, R. Piotrowicz, and T. J. Kunicki. 1988. J. Cell Biol. 107:1881-1891), we have identified a new fibronectin receptor that is identical to the integrin receptor alpha 4 beta 1. mAbs P3E3, P4C2, and P4G9 recognized epitopes on the alpha 4 subunit and completely inhibited the adhesion of peripheral blood and cultured T lymphocytes to a 38-kD tryptic fragment of plasma fibronectin containing the carboxy-terminal Heparin II domain and part of the type III connecting segment (IIICS). The ligand in IIICS for alpha 4 beta 1 was the CS-1 region previously defined as an adhesion site for melanoma cells. The functionally defined mAbs to alpha 4 partially inhibited T lymphocyte adhesion to intact plasma fibronectin and had no effect on their attachment to an 80-kD tryptic fragment containing the RGD (arg-gly-asp) adhesion sequence. mAbs (P1D6 and P1F8) to the previously described fibronectin receptor, alpha 5 beta 1, completely inhibited T lymphocyte adhesion to the 80-kD fragment but had no effect on their attachment to the 38-kD fragment or to CS-1. Both alpha 4 beta 1 and alpha 5 beta 1 localized to focal adhesions when fibroblasts that express these receptors were grown on fibronectin-coated surfaces. These findings demonstrated a specific interaction of both receptors with fibronectin at focal contacts. In conclusion, these findings show clearly that cultured T lymphocytes use two independent receptors during attachment to fibronectin and that (a) alpha 5 beta 1 is the receptor for the RGD containing cell adhesion domain, and (b) alpha 4 beta 1 is the receptor for a carboxy-terminal cell adhesion region containing the Heparin II and IIICS domains. Furthermore, these data also show that T lymphocytes express a clear preference for a region of molecular heterogeneity in IIICS (CS-1) generated by alternative splicing of fibronectin pre-mRNA and that alpha 4 beta 1 is the receptor for this adhesion site.

A proangiogenic peptide derived from vascular endothelial growth factor receptor-1 acts through α5β1 integrin

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3479-3488 ◽  
Author(s):  
Simonetta Soro ◽  
Angela Orecchia ◽  
Lucia Morbidelli ◽  
Pedro Miguel Lacal ◽  
Veronica Morea ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Growth Factors ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Α5β1 Integrin

Abstract Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor for growth factors of the VEGF family. Endothelial cells express a membrane-bound and a soluble variant of this protein, the latter being mainly considered as a negative regulator of VEGF-A signaling. We previously reported that the soluble form is deposited in the extracellular matrix produced by endothelial cells in culture and is able to promote cell adhesion and migration through binding to α5β1 integrin. In this study, we demonstrate that the Ig-like domain II of VEGFR-1, which contains the binding determinants for the growth factors, is involved in the interaction with α5β1 integrin. To identify domain regions involved in integrin binding, we designed 12 peptides putatively mimicking the domain II surface and tested their ability to inhibit α5β1-mediated endothelial cell adhesion to soluble VEGFR-1 and directly support cell adhesion. One peptide endowed with both these properties was identified and shown to inhibit endothelial cell migration toward soluble VEGFR-1 as well. This peptide directly binds α5β1 integrin, but not VEGF-A, inducing endothelial cell tubule formation in vitro and neoangiogenesis in vivo. Alanine scanning mutagenesis of the peptide defined which residues were responsible for its biologic activity and integrin binding.

scholarly journals CKAP4 Regulates Cell Migration via the Interaction with and Recycling of Integrin

2019 ◽  
Vol 39 (16) ◽  
Author(s):  
Yoshihito Osugi ◽  
Katsumi Fumoto ◽  
Akira Kikuchi
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Surface ◽  
Surface Membrane ◽  
Β1 Integrin ◽  
Cell Surface Membrane ◽  
Adhesion Sites ◽  
Endoplasmic Reticulum Protein ◽  
And Migration ◽  
Α5β1 Integrin

ABSTRACT Cytoskeleton-associated protein 4 (CKAP4) is an endoplasmic reticulum protein that is also present in the cell surface membrane, where it acts as a receptor for Dickkopf1 (DKK1). In this study, we found that CKAP4 interacts with β1 integrin and controls the recycling of α5β1 integrin independently of DKK1. In S2-CP8 cells, knockdown of CKAP4 but not DKK1 enlarged the size of cell adhesion sites and enhanced cell adhesion to fibronectin, resulting in decreased cell migration. When CKAP4 was depleted, the levels of α5 but not β1 integrin were increased in the cell surface membrane. A similar phenotype was observed in other cells expressing low levels of DKK1. In S2-CP8 cells, α5 integrin was trafficked with β1 integrin and CKAP4 to the lysosome or recycled with β1 integrin. In CKAP4-depleted cells, the internalization of α5β1 integrin was unchanged, but its recycling was upregulated. Knockdown of sorting nexin 17 (SNX17), a mediator of integrin recycling, abrogated the increased α5 integrin levels caused by CKAP4 knockdown. CKAP4 bound to SNX17, and its knockdown enhanced the recruitment of α5β1 integrin to SNX17. These results suggest that CKAP4 suppresses the recycling of α5β1 integrin and coordinates cell adhesion sites and migration independently of DKK1.

scholarly journals Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals

2007 ◽  
Vol 18 (11) ◽  
pp. 4519-4527 ◽  
Author(s):  
Wei-hui Guo ◽  
Yu-li Wang
Keyword(s):  
Cell Migration ◽  
Focal Adhesion ◽  
Mechanical Load ◽  
Focal Adhesions ◽  
Force Production ◽  
Retrograde Transport ◽  
Mechanical Stimuli ◽  
Adhesion Proteins ◽  
Mechanical Signals ◽  
Focal Adhesion Proteins

Recent studies suggest that mechanical signals mediated by the extracellular matrix play an essential role in various physiological and pathological processes; yet, how cells respond to mechanical stimuli remains elusive. Using live cell fluorescence imaging, we found that actin filaments, in association with a number of focal adhesion proteins, including zyxin and vasodilator-stimulated phosphoprotein, undergo retrograde fluxes at focal adhesions in the lamella region. This flux is inversely related to cell migration, such that it is amplified in fibroblasts immobilized on micropatterned islands. In addition, the flux is regulated by mechanical signals, including stretching forces applied to flexible substrates and substrate stiffness. Conditions favoring the flux share the common feature of causing large retrograde displacements of the interior actin cytoskeleton relative to the substrate anchorage site, which may function as a switch translating mechanical input into chemical signals, such as tyrosine phosphorylation. In turn, the stimulation of actin flux at focal adhesions may function as part of a feedback mechanism, regulating structural assembly and force production in relation to cell migration and mechanical load. The retrograde transport of associated focal adhesion proteins may play additional roles in delivering signals from focal adhesions to the interior of the cell.

scholarly journals RAP1-RAC1 Signaling Has an Important Role in Adhesion and Migration in HNSCC

2020 ◽  
Vol 99 (8) ◽  
pp. 959-968 ◽  
Author(s):  
M. Liu ◽  
R. Banerjee ◽  
C. Rossa ◽  
N.J. D’Silva
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Matrix Adhesion ◽  
Cell Matrix ◽  
And Migration ◽  
Rap1 Activation ◽  
Cell Matrix Adhesion ◽  
Α5β1 Integrin ◽  
Hnscc Cell ◽  
Cell Cell

Cell-cell adhesion is a key mechanism to control tissue integrity and migration. In head and neck squamous cell carcinoma (HNSCC), cell migration facilitates distant metastases and is correlated with poor prognosis. RAP1, a ras-like protein, has an important role in the progression of HNSCC. RAC1 is an integrin-linked, ras-like protein that promotes cell migration. Here we show that loss of cell-cell adhesion is correlated with inactivation of RAP1 confirmed by 2 different biochemical approaches. RAP1 activation is required for cell-matrix adhesion confirmed by adhesion to fibronectin-coated plates with cells that have biochemically activated RAP1. This effect is reversed when RAP1 is inactivated. In addition, RAP1GTP-mediated adhesion is only facilitated through α5β1 integrin complex and is not a function of either α5 or β1 integrin alone. Moreover, the inside-out signaling of RAP1 activation is coordinated with RAC1 activation. These findings show that RAP1 has a prominent role in cell-matrix adhesion via extracellular matrix molecule fibronectin-induced α5β1 integrin and supports a critical role for the RAP1/RAC1 signaling axis in HNSCC cell migration.

scholarly journals Migration regulates cellular mechanical states

2019 ◽  
Vol 30 (26) ◽  
pp. 3104-3111 ◽  
Author(s):  
Stephanie S. Chang ◽  
Andrew D. Rape ◽  
Stephanie A. Wong ◽  
Wei-hui Guo ◽  
Yu-li Wang
Keyword(s):  
Cell Migration ◽  
Focal Adhesion ◽  
Focal Adhesions ◽  
Traction Forces ◽  
Adhesion Proteins ◽  
Focal Adhesion Proteins

Cell migration has a profound effect on the generation of traction forces and the phosphorylation of focal adhesion proteins. The mechanism may involve the dynamic turnover of focal adhesions during cell migration and mechanical interactions between nascent and preexisting focal adhesions.

scholarly journals The alpha v beta 1 integrin functions as a fibronectin receptor but does not support fibronectin matrix assembly and cell migration on fibronectin

1993 ◽  
Vol 122 (1) ◽  
pp. 235-242 ◽  
Author(s):  
Z Zhang ◽  
AO Morla ◽  
K Vuori ◽  
JS Bauer ◽  
RL Juliano ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Attachment ◽  
Focal Adhesions ◽  
Cho Cell ◽  
Matrix Assembly ◽  
Fibronectin Receptor ◽  
Fibronectin Matrix ◽  
Beta 1 Integrin ◽  
Fibronectin Binding ◽  
Coated Surfaces

The fibronectin receptor, alpha 5 beta 1, has been shown to be required for fibronectin matrix assembly and plays an important role in cell migration on fibronectin. However, it is not clear whether other fibronectin binding integrins can take the place of alpha 5 beta 1 during matrix assembly and cell migration. To test this, we expressed the human alpha v subunit in the CHO cell line CHO-B2 that lacks the alpha 5 subunit. We found that the human alpha v combined with CHO cell beta 1 to form the integrin alpha v beta 1. Cells that expressed alpha v beta 1 attached to and spread well on fibronectin-coated dishes, but did so less well on vitronectin-coated dishes. This, along with other data, indicated that alpha v beta 1 functions as a fibronectin receptor in CHO-B2 cells. The alpha v beta 1-expressing cells failed to produce a fibronectin matrix or to migrate on fibronectin, although the same cells transfected with alpha 5 do produce a matrix and migrate on fibronectin. The affinity of the alpha v beta 1-expressing cells for fibronectin was fourfold lower than that of the alpha 5 beta 1-expressing cells. In addition, alpha v beta 1 was distributed diffusely throughout the cell surface, whereas alpha 5 beta 1 was localized to focal adhesions when cells were seeded onto fibronectin-coated surfaces. Thus, of the two fibronectin receptors, alpha v beta 1 and alpha 5 beta 1, only alpha 5 beta 1 supports fibronectin matrix assembly and promotes cell migration on fibronectin in the CHO-B2 cells. Possible reasons for this difference in the activities of alpha v beta 1 and alpha 5 beta 1 include the lower affinity of alpha v beta 1 for fibronectin and the failure of this integrin to localize in adhesion plaques on a fibronectin substrate. These results show that two integrins with similar ligand specificities and cell attachment functions may be quite different in their ability to support fibronectin matrix assembly and cell motility on fibronectin.

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