Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton

Nandelstadh, Pernilla von; Gucciardo, Erika; Lohi, Jouko; Li, Rui; Sugiyama, Nami; Carpén, Olli; Lehti, Kaisa

doi:10.1091/mbc.e13-11-0667

Cited by 43 publications

(41 citation statements)

References 70 publications

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“…Palladin is upregulated in cells that are actively migrating such as in developing vertebrate embryos [1], along a wound edge [2], during metastatic invasion [3] and in the development of cardiovascular diseases [4, 5] [6] [7]. Conversely cells that are depleted of palladin have defects in cell motility [8], display disorganized actin cytoskeleton architecture [9] and a significant decrease in the amount of polymerized actin [10].…”

Section: Introductionmentioning

confidence: 99%

Actin polymerization is stimulated by actin cross-linking protein palladin

Gurung

Yadav

Brungardt

et al. 2016

Biochemical Journal

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The actin scaffold protein palladin regulates both normal cell migration and invasive cell motility, processes that require the coordinated regulation of actin dynamics. However, the potential effect of palladin on actin dynamics has remained elusive. Here we show that the actin binding immunoglobulin-like domain of palladin, which is directly responsible for both actin binding and bundling, also stimulates actin polymerization in vitro. Palladin eliminated the lag phase that is characteristic of the slow nucleation step of actin polymerization. Furthermore, palladin dramatically reduced depolymerization, slightly enhanced the elongation rate, and did not alter the critical concentration. Microscopy and in vitro crosslinking assays reveal differences in actin bundle architecture when palladin is incubated with actin before or after polymerization. These results suggest a model whereby palladin stimulates a polymerization-competent form of G-actin, akin to metal ions, either through charge neutralization or conformational changes.

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Section: Introductionmentioning

confidence: 99%

Actin polymerization is stimulated by actin cross-linking protein palladin

Gurung

Yadav

Brungardt

et al. 2016

Biochemical Journal

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“…In invasive cell pseudopodia, the collagenase activity of MT1-MMP depends upon interacting with palladin which connects it to the actin cytoskeleton (von Nandelstadh et al, 2014) and upon dynamic homodimerization regulated by the reorganization of the actin cytoskeleton by Rho GTPases (Itoh et al, 2011). This self-association that can occur at the leading but not trailing cell surfaces appears to depend on the hemopexin-like (HPX) (Itoh et al, 2001), transmembrane, and cytoplasmic domains (Itoh et al, 2008; Lehti et al, 2002; Rozanov et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…These truncations disrupted assembly of MT1-MMP into a collagenolytic form in the plasma membrane. This was attributed to defective homodimerization (Itoh et al, 2006), but the truncations may also have disturbed other interactions that facilitate its collagenase activity, such as with cell adhesion complexes which contain β1-integrins (Woskowicz et al, 2013) and with the cytoskeleton via palladin (von Nandelstadh et al, 2014). The soluble ectodomain of MT1-MMP is monomeric and very active in collagen degradation, propelling it in one direction along the collagen fibril, analogous to MMP-1 (Collier et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Transient Collagen Triple Helix Binding to a Key Metalloproteinase in Invasion and Development

et al. 2015

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SUMMARY Skeletal development and invasion by tumor cells depends on proteolysis of collagen by the pericellular metalloproteinase MT1-MMP. Its hemopexin-like (HPX) domain binds to collagen substrates to facilitate their digestion. Spin labeling and paramagnetic NMR detection have revealed how the HPX domain docks to collagen I-derived triple-helix. Mutations impairing triple-helical peptidase activity corroborate the interface. Saturation transfer difference NMR suggests rotational averaging around the longitudinal axis of the triple-helical peptide. Part of the interface emerges as unique and potentially targetable for selective inhibition. The triple-helix crosses the junction of blades I and II at a 45° angle to the symmetry axis of the HPX domain, placing the scissile Gly~Ile bond near the HPX domain and shifted ~25 Å from MMP-1 complexes. This raises the question of the MT1-MMP catalytic domain folding over the triple-helix during catalysis, a possibility accommodated by the flexibility between domains suggested by AFM images.

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“…Palladin is an actin associated Ig-domain protein that is overexpressed in many cancers and particularly in CAFs (26)(27)(28)(29)(30)(31)(32). Palladin has been shown to regulate actin dynamics and adhesion formation (30,32).…”

Section: Introductionmentioning

confidence: 99%

Palladin Mediates Stiffness-Induced Fibroblast Activation in the Tumor Microenvironment

McLane

Ligon

2015

Biophysical Journal

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Mechanical properties of the tumor microenvironment have emerged as key factors in tumor progression. It has been proposed that increased tissue stiffness can transform stromal fibroblasts into carcinoma-associated fibroblasts. However, it is unclear whether the three to five times increase in stiffness seen in tumor-adjacent stroma is sufficient for fibroblast activation. In this study we developed a three-dimensional (3D) hydrogel model with precisely tunable stiffness and show that a physiologically relevant increase in stiffness is sufficient to lead to fibroblast activation. We found that soluble factors including CC-motif chemokine ligand (CCL) chemokines and fibronectin are necessary for this activation, and the combination of C-C chemokine receptor type 4 (CCR4) chemokine receptors and β1 and β3 integrins are necessary to transduce these chemomechanical signals. We then show that these chemomechanical signals lead to the gene expression changes associated with fibroblast activation via a network of intracellular signaling pathways that include focal adhesion kinase (FAK) and phosphoinositide 3-kinase (PI3K). Finally, we identify the actin-associated protein palladin as a key node in these signaling pathways that result in fibroblast activation.

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Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton

Cited by 43 publications

References 70 publications

Actin polymerization is stimulated by actin cross-linking protein palladin

Actin polymerization is stimulated by actin cross-linking protein palladin

Transient Collagen Triple Helix Binding to a Key Metalloproteinase in Invasion and Development

Palladin Mediates Stiffness-Induced Fibroblast Activation in the Tumor Microenvironment

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