Selective regulation of integrin–cytoskeleton interactions by the tyrosine kinase Src

Felsenfeld, Dan P.; Schwartzberg, Pamela L.; Venegas, Ana M.; Tse, Rosa Pui-Ying; Sheetz, Michael P.

doi:10.1038/12021

Cited by 243 publications

(214 citation statements)

References 37 publications

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“…In control cells, the interaction of the vitronectin receptor with the cytoskeleton is reinforced. In contrast, the vitronectin receptor becomes reinforced in srcÀ/À fibroblasts (Felsenfeld et al, 1999). These results suggest that Src functions in inhibiting reinforcement of the vitronectin receptor.…”

Section: Control Of Integrin Attachment To the Cytoskeletonmentioning

confidence: 40%

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The interplay between Src and integrins in normal and tumor biology

2004

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Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

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Section: Control Of Integrin Attachment To the Cytoskeletonmentioning

confidence: 40%

“…srcÀ/À fibroblasts exhibit reduced adhesion and delayed spreading relative to Src-expressing fibroblasts (Kaplan et al, 1995;Felsenfeld et al, 1999). Osteoclasts isolated from srcÀ/À mice show reduced adhesion and spreading on vitronectin (Lakkakorpi et al, 2001).…”

Section: Biological Processes Mediated By Src-integrin Signalingmentioning

confidence: 99%

The interplay between Src and integrins in normal and tumor biology

2004

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“…However, it remains largely mysterious how mechanical stimuli are transmitted into biochemical signals. Src is known to regulate the integrin-cytoskeleton interaction 2 , which is essential for the transduction of mechanical stimuli [3][4][5] . Using fluorescent resonance energy transfer (FRET), here we develop a genetically encoded Src reporter that enables the imaging and quantification of spatio-temporal activation of Src in live cells.…”

mentioning

confidence: 99%

Visualizing the mechanical activation of Src

Wang¹,

Botvinick

Zhao³

et al. 2005

Nature

624

589

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“…Src family kinase activation and tyrosine phosphorylation both have roles in early focal adhesion-associated mechanosensing (17). Tyrosine phosphorylation of focal adhesion kinase (FAK) assists in the recruitment and binding of focal adhesion proteins by regulating protein-protein interactions in proteins that contain the Src homology 2 (SH2) (32), whereas Src family kinase activation and interaction with FAK initiates tyrosine phosphorylation of paxillin and p130Cas, leading to Rac-dependent focal adhesion turnover and cell migration (12,34). …”

mentioning

confidence: 99%

Force-induced focal adhesion translocation: effects of force amplitude and frequency

Mack

Kaazempur-Mofrad²,

Karcher³

et al. 2004

American Journal of Physiology-Cell Physiology

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. Force-induced focal adhesion translocation: effects of force amplitude and frequency. Am J Physiol Cell Physiol 287: C954 -C962, 2004. First published June 9, 2004 10.1152/ajpcell. 00567.2003.-Vascular endothelial cells rapidly transduce local mechanical forces into biological signals through numerous processes including the activation of focal adhesion sites. To examine the mechanosensing capabilities of these adhesion sites, focal adhesion translocation was monitored over the course of 5 min with GFPpaxillin while applying nN-level magnetic trap shear forces to the cell apex via integrin-linked magnetic beads. A nongraded steady-load threshold for mechanotransduction was established between 0.90 and 1.45 nN. Activation was greatest near the point of forcing (Ͻ7.5 m), indicating that shear forces imposed on the apical cell membrane transmit nonuniformly to the basal cell surface and that focal adhesion sites may function as individual mechanosensors responding to local levels of force. Results from a continuum, viscoelastic finite element model of magnetocytometry that represented experimental focal adhesion attachments provided support for a nonuniform force transmission to basal surface focal adhesion sites. To further understand the role of force transmission on focal adhesion activation and dynamics, sinusoidally varying forces were applied at 0.1, 1.0, 10, and 50 Hz with a 1.45 nN offset and a 2.25 nN maximum. At 10 and 50 Hz, focal adhesion activation did not vary with spatial location, as observed for steady loading, whereas the response was minimized at 1.0 Hz. Furthermore, applying the tyrosine kinase inhibitors genistein and PP2, a specific Src family kinase inhibitor, showed tyrosine kinase signaling has a role in force-induced translocation. These results highlight the mutual importance of force transmission and biochemical signaling in focal adhesion mechanotransduction. mechanotransduction; endothelial cell; paxillin; viscoelastic model MECHANOTRANSDUCTION IS AN essential function of the cell, controlling its growth, proliferation, protein synthesis, and gene expression (8,18). Extensive data exist documenting the cellular responses to external force (15, 41, 44), but less is known about how force affects rapid biological signaling. Although integrins/focal adhesion sites (42), cytoskeleton constituents, G proteins (6), ion channels, intercellular junction proteins, and membrane biomolecules have all been identified as potential mechanosensors (6,16,42,43), we know little about the force level and frequency-dependent thresholds required to initiate mechanotransduction or the role of intracellular force transmission on mechanosensor activation. Biological readouts used to study mechanotransduction range from long-term gene expression and cell morphology changes (8, 26) to rapid variations in intracellular ion concentration and protein activity (8,26,42). Morphological and gene expression comparisons provide a robust marker of mechanotransduction, but the response is slow on the scale of hours, a...

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Selective regulation of integrin–cytoskeleton interactions by the tyrosine kinase Src

Cited by 243 publications

References 37 publications

The interplay between Src and integrins in normal and tumor biology

The interplay between Src and integrins in normal and tumor biology

Visualizing the mechanical activation of Src

Force-induced focal adhesion translocation: effects of force amplitude and frequency

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