Ligand binding regulates the directed movement of β1 integrins on fibroblasts

Felsenfeld, Dan P.; Choquet, Daniel; Sheetz, Michael P.

doi:10.1038/383438a0

Cited by 209 publications

(159 citation statements)

References 22 publications

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“…uPA-R is a major binding protein to the vitronectin-rich extracellular matrix (Kanse et al, 1996). It (Felsenfeld et al, 1996;Wei et al, 1996). Indeed, in addition to breast cancer, a strong impact on prognosis of uPA content in tumour tissue has been observed in many other malignancies, e.g.…”

Section: Discussionmentioning

confidence: 99%

Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer

Schmitt

Thomssen²,

Ulm³

et al. 1997

Br J Cancer

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Summary In breast cancer, several investigations have demonstrated that the tumour biological factors uPA urokinase-type plasminogen activator) and its inhibitor PAI-1 are statistically independent, strong prognostic factors for disease-free (DFS) and overall survival (OS). However, statistical analyses performed for varying follow-up periods suggested a time variation of prognostic strength. We therefore investigated the time-dependent prognostic power of uPA, PAI-1 and steroid hormone receptor status applying the time-varying coefficient model of Gray. uPA and PAI-1 were analysed by enzyme-linked immunosorbent assay in tumour tissue extracts from 314 breast cancer patients. Hormone receptors (oestrogen and progesterone) were determined by radioligand binding or by immunohistochemistry. Univariate and multivariate analyses (Cox proportional hazards model) of DFS and OS were performed for all patients, including 147 node-negative patients. Median follow-up of patients still alive at time of analysis (n = 232) was 58 months. Although initially of high prognostic impact, a continuous decrease over time in the prognostic power of hormone receptor status and uPA was observed. In contrast, the prognostic impact of PAI-1 increased over time and reached similar strength as the lymph node status. The time-dependent risk profile of prognostic factors may have important clinical implications in regard to follow-up and patients' individual risk situation. Evaluation of time dependency of prognostic factors may also give a more profound insight into the dynamics of breast cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer

Schmitt

Thomssen²,

Ulm³

et al. 1997

Br J Cancer

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“…How could myosin II activity induce integrin clustering? Although unbound integrins are freely diffusive in the membrane plane, ligand binding promotes rapid attachment of integrins to actin filaments (Felsenfeld et al, 1996). Myosin II is an effective F-actin cross-linker (Laevsky and Knecht, 2003), and myosin-driven bundling and alignment of actin filaments carrying ligand-bound integrin complexes could then lead to the clustering of integrin-cytoskeleton complexes (Chrzanowska-Wodnicka and Burridge, 1996).…”

Section: Discussionmentioning

confidence: 99%

Revealing Early Steps of α₂β₁Integrin-mediated Adhesion to Collagen Type I by Using Single-Cell Force Spectroscopy

Taubenberger

Cisneros

Friedrichs

et al. 2007

MBoC

192

197

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We have characterized early steps of ␣ 2 ␤ 1 integrin-mediated cell adhesion to a collagen type I matrix by using single-cell force spectroscopy. In agreement with the role of ␣ 2 ␤ 1 as a collagen type I receptor, ␣ 2 ␤ 1 -expressing Chinese hamster ovary (CHO)-A2 cells spread rapidly on the matrix, whereas ␣ 2 ␤ 1 -negative CHO wild-type cells adhered poorly. Probing CHO-A2 cell detachment forces over a contact time range of 600 s revealed a nonlinear adhesion response. During the first 60 s, cell adhesion increased slowly, and forces associated with the smallest rupture events were consistent with the breakage of individual integrin-collagen bonds. Above 60 s, a fraction of cells rapidly switched into an activated adhesion state marked by up to 10-fold increased detachment forces. Elevated overall cell adhesion coincided with a rise of the smallest rupture forces above the value required to break a single-integrin-collagen bond, suggesting a change from single to cooperative receptor binding. Transition into the activated adhesion mode and the increase of the smallest rupture forces were both blocked by inhibitors of actomyosin contractility. We therefore propose a two-step mechanism for the establishment of ␣ 2 ␤ 1 -mediated adhesion as weak initial, single-integrin-mediated binding events are superseded by strong adhesive interactions involving receptor cooperativity and actomyosin contractility. INTRODUCTIONIntegrins are a family of ␣/␤-heterodimeric receptors involved in cell-cell adhesion and cell attachment to the extracellular matrix (Hynes, 1992). In adherent cells, integrins are often arranged into highly organized structures, such as focal complexes, focal adhesions, and fibrillar adhesions . In these mature adhesive contacts, integrins are linked to the actin cytoskeleton via their intracellular domains and a multitude of adapter proteins, such as vinculin, talin, and ␣-actinin (Zamir and Geiger, 2001). Whereas the molecular composition of integrin complexes and signaling pathways controlling their macroscopic assembly or disassembly have been analyzed in detail, less is known about the early molecular events leading to the formation of integrin-based adhesion.Generally, integrin-mediated adhesion is thought to be initiated on the cell membrane by the engagement of individual integrin dimers with their respective ligand (Lotz et al., 1989;Gallant and Garcia, 2006). The number of receptorligand pairs may then grow by increasing the cell-substrate contact area and by receptor diffusion within that zone. Subsequent adhesion strengthening occurs through integrin clustering and linkage to the cytoskeleton. In addition, the ligand affinity of the integrins may increase as a result of intracellular regulatory pathways (Hughes and Pfaff, 1998). At a later stage, the assembly of higher-order integrincytoskeletal complexes requires actomyosin-driven contractility under the control of the small guanosine triphosphatase (GTPase) RhoA (Chrzanowska-Wodnicka and Burridge, 1996) and its downstream target Rho-assoc...

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“…␤ 1 Integrin Signaling Stimulates PKA Activity-In response to a chemoattractant such as LPA, new ␤ 1 integrin-mediated contacts are formed at the leading edge to generate the traction necessary for migration (1,21). Given that both ␤ 1 integrins (11) and PKA ( Fig.…”

Section: Fig 3 Rac Activation By ␤ 1 Integrins Requires Pka a And Bmentioning

confidence: 99%

Protein Kinase A Regulates Rac and Is Required for the Growth Factor-stimulated Migration of Carcinoma Cells

O’Connor¹,

Mercurio

2001

Journal of Biological Chemistry

128

110

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Members of theIn this study, we report that the migration of breast and squamous carcinoma cells toward either lysophosphatidic acid or epidermal growth factor involves not only phosphodiesterase activity but also cooperative signaling from PKA. Furthermore, we demonstrate that Rac1 activation in response to chemoattractant or ␤ 1 integrin clustering is regulated by PKA and that Rac1 is required for this migration. Also, we find that ␤ 1 integrin signaling stimulates the rapid and transient activation of PKA. A novel implication of these findings is that carcinoma cell migration is controlled by cAMP-dependent as well as cAMP inhibitory signaling mechanisms.

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Ligand binding regulates the directed movement of β1 integrins on fibroblasts

Cited by 209 publications

References 22 publications

Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer

Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer

Revealing Early Steps of α₂β₁Integrin-mediated Adhesion to Collagen Type I by Using Single-Cell Force Spectroscopy

Protein Kinase A Regulates Rac and Is Required for the Growth Factor-stimulated Migration of Carcinoma Cells

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Ligand binding regulates the directed movement of β1 integrins on fibroblasts

Cited by 209 publications

References 22 publications

Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer

Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer

Revealing Early Steps of α2β1Integrin-mediated Adhesion to Collagen Type I by Using Single-Cell Force Spectroscopy

Protein Kinase A Regulates Rac and Is Required for the Growth Factor-stimulated Migration of Carcinoma Cells

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Revealing Early Steps of α₂β₁Integrin-mediated Adhesion to Collagen Type I by Using Single-Cell Force Spectroscopy