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. 2020:355:1-52.
doi: 10.1016/bs.ircmb.2020.05.003. Epub 2020 Aug 6.

Paxillin family of focal adhesion adaptor proteins and regulation of cancer cell invasion

Kyle M Alpha  1 , Weiyi Xu  1 , Christopher E Turner  2
Affiliations

Paxillin family of focal adhesion adaptor proteins and regulation of cancer cell invasion

Kyle M Alpha et al. Int Rev Cell Mol Biol. 2020.

Abstract

The paxillin family of proteins, including paxillin, Hic-5, and leupaxin, are focal adhesion adaptor/scaffolding proteins which localize to cell-matrix adhesions and are important in cell adhesion and migration of both normal and cancer cells. Historically, the role of these proteins in regulating the actin cytoskeleton through focal adhesion-mediated signaling has been well documented. However, studies in recent years have revealed additional functions in modulating the microtubule and intermediate filament cytoskeletons to affect diverse processes including cell polarization, vesicle trafficking and mechanosignaling. Expression of paxillin family proteins in stromal cells is also important in regulating tumor cell migration and invasion through non-cell autonomous effects on the extracellular matrix. Both paxillin and Hic-5 can also influence gene expression through a variety of mechanisms, while their own expression is frequently dysregulated in various cancers. Accordingly, these proteins may serve as valuable targets for novel diagnostic and treatment approaches in cancer.

Keywords: Actin; Hic-5; Invasion; Mechanosignaling; Migration; Paxillin; Plasticity; Stroma.

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Figures

Fig. 1
Fig. 1
Domain structure of paxillin family members and key binding partners. The three paxillin family members, paxillin, Hic-5 and leupaxin, exhibit extensive homology within the N-terminal leucine aspartate-rich LD motifs, the C-terminal LIM domains and key phosphorylation sites. These domains interact with shared, as well as distinct, binding partners in their role as adapter/scaffold proteins to regulate focal adhesion organization and signaling to control cytoskeletal remodeling and cell migration. A selection of key binding partners is indicated.
Fig. 2
Fig. 2
Paxillin and Hic-5 play opposing roles in regulating tumor cell 3D migration phenotype. Tumor cells with high ratios of paxillin:Hic-5 expression (low Hic-5 levels, since paxillin expression is fairly consistent among tumor cells) more commonly exhibit amoeboid migration, which requires RhoA-mediated contractility. These cells have limited, or no 3D adhesions; any adhesions that form tend to disassemble rapidly. Paxillin may sequester inactive vinculin to promote adhesion disassembly. Amoeboid cells migrate by squeezing through existing spaces in the ECM via F-actin-rich plasma membrane blebs. Conversely, tumor cells with low paxillin:Hic-5 ratios (high Hic-5 levels) can exhibit plasticity and are more likely to exhibit mesenchymal migration, which is Rac1-mediated. These cells form relatively robust, stable 3D adhesions, and use MMPs to degrade the ECM. In these cells, Hic-5 binds active vinculin to promote 3D adhesion formation and stabilization. It is unclear precisely how paxillin versus Hic-5 “activity” is regulated to promote dynamic migration plasticity.
Fig. 3
Fig. 3
Hic-5 contributes to the formation and dynamics of invadopodia and higher order rosette structures. (A) Hic-5 is upregulated during TGF-β-induced epithelial-mesenchymal transition (EMT) to promote RhoA/ROCK-mediated actin stress fiber ormation. (B) Hic-5 upregulation in normal mammary epithelial cells also promotes the formation of matrix-degrading invadopodia, via Src, Rac1 and RhoC, leading to increased cell invasion. Both paxillin and Hic-5 localize to, and regulate, the dynamics of individual invadopodia. Hic-5 also promotes the coalescence of numerous invadopodia into higher order rosettes in Src-transformed cells, involving formin-regulated actin assembly. Rapid rosette disassembly is Hic-5-dependent and is frequently associated with bursts of Rac1-driven lamellipodial extensions and the formation of new focal adhesions.
Fig. 4
Fig. 4
Paxillin-dependent changes in microtubule acetylation and their effect on cell polarity, vesicle trafficking, and Golgi/centrosome cohesion. (A) Paxillin promotes front-rear polarity in mesenchymal cells through its regulation of microtubule (MT) acetylation. Paxillin binding to, and inhibition of the deacetylase HDAC6 promotes MT acetylation. Paxillin-dependent MT acetylation is also required for Golgi cohesion and positioning, as well as vesicle trafficking of pro-migratory factors, such as integrins from the endoplasmic reticulum via the Golgi apparatus to the plasma membrane. Microtubule targeting to focal adhesions promotes their turnover in a paxillin-dependent manner. Although primarily a focal adhesion protein, paxillin also localizes to the centrosome and is required for its cohesion and polarization during migration. (B) Paxillin also plays a key role in maintaining apical-basal polarity and lumen formation in normal epithelia through regulation of HDAC6 to control microtubule acetylation. Apically enriched acetylated microtubules facilitate basal-apical trafficking, cell shape and the integrity of cell-cell junctions.
Fig. 5
Fig. 5
Hic-5 expression in cancer-associated fibroblasts is required for effective extracellular matrix deposition and organization. Hic-5 expression promotes increased RhoA-mediated contractility in cancer-associated fibroblasts (CAFs), leading to a more “activated” myofibroblast-like phenotype. Hic-5 knockout CAFs are deficient in extracellular matrix (ECM) deposition and remodeling in 2D and 3D when compared to those expressing Hic-5; this is at least partially mediated by diminished fibronectin fiber assembly at fibrillar adhesions involving Src-regulated Hic-5 interactions with tensin. Furthermore, Hic-5 knockout CAFs exhibit a central F-actin “hole” and a collapsed vimentin intermediate filament cytoskeleton. Both of these phenotypes can be mimicked in Hic-5-expressing CAFs by pharmacologic formin inhibition or rescued in Hic-5 knockout CAFs by pharmacologic inhibition of the RhoGTPase Cdc42. Hic-5-dependent deposition and remodeling of the stromal ECM in vivo promotes non-cell autonomous signaling in the tumor cells to stimulate their invasion and dissemination.
Fig. 6
Fig. 6
Expression of paxillin family members varies among cancers. Numbers in paxillin, Hic-5, and leupaxin columns indicate how many studies show increased or decreased mRNA expression of that gene in tumor relative to normal tissue (thresholds for inclusion: P <0.0001, fold change ≥ 2, top 10% gene rank). Darker cell color indicates higher gene rank percentile for the studies in that cell. Data were obtained from the Oncomine cancer expression database (Thermo Fisher Scientific Inc., www.oncomine.org).
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