Diverse Roles for the Paxillin Family of Proteins in Cancer

Deakin, Nicholas O.; Pignatelli, Jeanine; Turner, Christopher E.

doi:10.1177/1947601912458582

Cited by 69 publications

(72 citation statements)

References 148 publications

(221 reference statements)

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“…Interestingly, our finding that soluble tumor-derived factors decreased paxillin and NRP2 expression in vitro and in vivo is consistent with past reports that have shown that paxillin is decreased in lung, breast and colorectal tumors, among others (Deakin et al, 2012;Salgia et al, 1999;Yang et al, 2010). This seems to be controversial because paxillin expression has also been reported to be elevated in lung, prostate, breast, cervical and other tumors (Deakin et al, 2012;Jagadeeswaran et al, 2008;Mackinnon et al, 2011;Salgia et al, 1999;Sen et al, 2012).…”

Section: Discussionsupporting

confidence: 77%

“…Paxillin is a multifunctional multidomain focal adhesion adaptor protein that is phosphorylated by Src and focal adhesion kinase (FAK) (Tachibana et al, 1995;Turner et al, 1990), and associates with many other focal adhesion proteins and signaling molecules (Brown and Turner, 2004;Deakin et al, 2012;Hagel et al, 2002;Sero et al, 2012;Turner et al, 1990). It can positively and negatively regulate cell migration depending on whether it is located at the leading edge (Nayal et al, 2006) or tail end (Nishiya et al, 2005) of the cell.…”

Section: Introductionmentioning

confidence: 99%

“…Paxillin-knockout mice are embryonic lethal because of developmental defects in the mesoderm (Hagel et al, 2002), and paxillin knockdown causes defects in embryonic stem cell spreading (Wade et al, 2002) and enhances HeLa cell migration (Yano et al, 2004). Interestingly, paxillin mutations and changes in protein expression are also associated with alterations in the malignant progression of many tumors (Deakin et al, 2012), including breast (Madan et al, 2006;Short et al, 2007), lung (Jagadeeswaran et al, 2008;Mackinnon et al, 2011;Salgia et al, 1999), prostate (Sen et al, 2012), melanoma (Velasco-Velázquez et al, 2008) and colorectal cancer (Yang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression

German

Mammoto

Jiang

et al. 2014

Journal of Cell Science

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Although a number of growth factors and receptors are known to control tumor angiogenesis, relatively little is known about the mechanism by which these factors influence the directional endothelial cell migration required for cancer microvessel formation. Recently, it has been shown that the focal adhesion protein paxillin is required for directional migration of fibroblasts in vitro. Here, we show that paxillin knockdown enhances endothelial cell migration in vitro and stimulates angiogenesis during normal development and in response to tumor angiogenic factors in vivo. Paxillin produces these effects by decreasing expression of neuropilin 2 (NRP2). Moreover, soluble factors secreted by tumors that stimulate vascular ingrowth, including vascular endothelial growth factor (VEGF), also decrease endothelial cell expression of paxillin and NRP2, and overexpression of NRP2 reverses these effects. These results suggest that the VEGF-paxillin-NRP2 pathway could represent a new therapeutic target for cancer and other angiogenesis-related diseases.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression

German

Mammoto

Jiang

et al. 2014

Journal of Cell Science

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“…6, D and E). It is well known that the phosphorylation of paxillin is required for cell adhesion and invasion (34). Therefore, these data suggested that Yes is involved in the invasion activities via the activation of paxillin, a key protein as a downstream target of Yes in G(ϩ) astrocytes.…”

Section: Figure 2 Establishment Of Gd3-positive Cells and Gd3-negatimentioning

confidence: 80%

Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase

Ohkawa

Momota

Kato

et al. 2015

Journal of Biological Chemistry

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Background: Roles of GD3 in gliomas are not well understood. Results: PDGF receptor ␣ was identified as a GD3-associated molecule by enzyme-mediated activation of radical sources and mass spectrometry, and its association with GD3 and Yes leads to increased invasiveness. Conclusion: GD3 enhances invasiveness by forming a molecular complex. Significance: GD3/PDGF receptor ␣⅐Yes complex is a potential target for glioma therapy.

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“…These data are consistent with our observations in 3D that local tension drives protrusion extension and migration and suggest that stress asymmetries play a role in a variety of cell processes in vivo. Because paxillin appears to mediate cellular responses to IF, and it is also known to be involved in tumor progression and metastasis in many types of cancer (44), modulation of paxillin levels or activity could offer a therapeutic strategy for treating metastatic carcinoma. Importantly, in solid tumors, interstitial fluid flow emanates from the vasculature, and consequently, tumor cells in close proximity to blood vessels will be directed via rheotaxis toward the leaky vasculature, which is the point of maximum fluid pressure (45).…”

Section: Discussionmentioning

confidence: 99%

Mechanotransduction of fluid stresses governs 3D cell migration

Polacheck

German

Mammoto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

231

215

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Solid tumors are characterized by high interstitial fluid pressure, which drives fluid efflux from the tumor core. Tumor-associated interstitial flow (IF) at a rate of ∼3 μm/s has been shown to induce cell migration in the upstream direction (rheotaxis). However, the molecular biophysical mechanism that underlies upstream cell polarization and rheotaxis remains unclear. We developed a microfluidic platform to investigate the effects of IF fluid stresses imparted on cells embedded within a collagen type I hydrogel, and we demonstrate that IF stresses result in a transcellular gradient in β1-integrin activation with vinculin, focal adhesion kinase (FAK), FAK PY397 , F actin, and paxillindependent protrusion formation localizing to the upstream side of the cell, where matrix adhesions are under maximum tension. This previously unknown mechanism is the result of a force balance between fluid drag on the cell and matrix adhesion tension and is therefore a fundamental, but previously unknown, stimulus for directing cell movement within porous extracellular matrix.mechanobiology | breast cancer | metastasis I ntegrins and associated focal adhesion (FA) proteins form a tension-sensitive mechanical link between the extracellular matrix (ECM) and the cytoskeleton, and serve as key components in the signaling cascade by which cells transduce mechanical signals into biological responses (mechanotransduction) (1, 2). Contractile stresses generated by the cell are balanced by tractions at cell-substrate adhesions, and the FA protein vinculin accumulates at regions of high substrate stress (3, 4). The FA protein paxillin colocalizes with vinculin (4) and mediates β1-integrin FA turnover through interaction with FA kinase (FAK) (5). The FAK-paxillin signaling axis recruits vinculin to β1 integrins at regions of high matrix adhesion tension (6), and paxillin-a key mechanosensor (7)-mediates protrusion formation at regions of high stress on 2D substrates (8), and FAK-paxillin-vinculin signaling is required for mechanosensing and durotaxis (9).The tumor microenvironment imparts mechanical and chemical signals on tumor and stromal cells (10), and advanced breast carcinomas are characterized by high interstitial fluid pressure (11), an indicator of poor prognosis (12). This elevated fluid pressure drives interstitial flow (IF) and alters chemical transport within the tumor (13), and IF influences tumor cell migration through the generation of autocrine chemokine gradients (14). Equally important, although not as well understood, is the physical drag imparted on the ECM and constitutive cells (15) by IF, which is analogous to the FA-activating shear stresses generated on endothelial cells by hemodynamic forces (16). With endothelial cells, shear stress can be the dominant mechanical stimulus that induces FAK activation and cytoskeletal remodeling; however, for cells embedded within a porous matrix scaffold, the ratio of the force due to the pressure drop across the cell to the total shear force is inversely proportional to hydrogel p...

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Diverse Roles for the Paxillin Family of Proteins in Cancer

Cited by 69 publications

References 148 publications

Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression

Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression

Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase

Mechanotransduction of fluid stresses governs 3D cell migration

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