p53 Suppresses Src-Induced Podosome and Rosette Formation and Cellular Invasiveness through the Upregulation of Caldesmon

Mukhopadhyay, Utpal K.; Eves, Robert; Jia, Lilly; Mooney, Patrick; Mak, Alan S.

doi:10.1128/mcb.01816-08

Cited by 68 publications

(88 citation statements)

References 61 publications

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“…There is evidence that h-CaD expression enhances stress fiber stability and reduces cell motility in non-muscle cells (Castellino et al, 1992;Castellino et al, 1995;Eppinga et al, 2006;Li et al, 2004;Mayanagi et al, 2008;Mirzapoiazova et al, 2005). Moreover, CaD expression induced by p53 suppresses Src-kinase-dependent podosome formation, which inhibits fibroblast and rat aortic SMC migration (Mukhopadhyay et al, 2009). By contrast, HeLa-l-CaD expression in endothelial cells and endothelial progenitor cells in the vasculature of various human tumors promotes cell migration for vasculogenesis and angiogenesis during tumor development (Zheng et al, 2004;Zheng et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Sox4-mediated caldesmon expression facilitates skeletal myoblast differentiation

Jang

Kim

et al. 2013

Journal of Cell Science

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Summary Caldesmon (CaD), which was originally identified as an actin-regulatory protein, is involved in the regulation of diverse actin-related signaling processes, including cell migration and proliferation, in various cells. The cellular function of CaD has been studied primarily in the smooth muscle system; nothing is known about its function in skeletal muscle differentiation. In this study, we found that the expression of CaD gradually increased as differentiation of C2C12 myoblasts progressed. Silencing of CaD inhibited cell spreading and migration, resulting in a decrease in myoblast differentiation. Promoter analysis of the caldesmon gene (Cald1) and gel mobility shift assays identified Sox4 as a major trans-acting factor for the regulation of Cald1 expression during myoblast differentiation. Silencing of Sox4 decreased not only CaD protein synthesis but also myoblast fusion in C2C12 cells and myofibril formation in mouse embryonic muscle. Overexpression of CaD in Sox4-silenced C2C12 cells rescued the differentiation process. These results clearly demonstrate that CaD, regulated by Sox4 transcriptional activity, contributes to skeletal muscle differentiation.

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Section: Discussionmentioning

confidence: 99%

Sox4-mediated caldesmon expression facilitates skeletal myoblast differentiation

Jang

Kim

et al. 2013

Journal of Cell Science

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“…Formation of podosomes is generally correlated with invasive migration (Mukhopadhyay et al, 2009;Linder, 2007;Seals et al, 2005). However, the relationship between podosome rosettes and invasion has not been defined in Src-transformed cells.…”

Section: Invasive Migration Of Mabp1-deficient Cellsmentioning

confidence: 99%

“…Both podosome dots and rosettes are capable of degrading the ECM (Mukhopadhyay et al, 2009;Linder, 2007;Seals et al, 2005). To determine whether mAbp1-deficient cells retain their capacity to degrade the ECM, we plated cells on coverslips coated with a mixed substrate of fibronectin and Alexa-Fluor-568-conjugated gelatin.…”

Section: Effects Of Mabp1 On Degradation Of the Extracellular Matrixmentioning

confidence: 99%

Src-mediated phosphorylation of mammalian Abp1 (DBNL) regulates podosome rosette formation in transformed fibroblasts

Boateng

Cortesio

Huttenlocher

2012

Journal of Cell Science

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There were errors published in J. Cell Sci. 125, 1329-1341.All mentions of Tyr340 and Tyr350 should read Tyr337 and Tyr347, respectively.In addition, the double phospho-mutant should be mCherry-mAbp1(Y337E,Y347F).The corrected legend to Fig. 9 appears below. Fig. 9. Model of mAbp1 regulation of podosome formation and invasive migration. mAbp1 binds to filamentous actin and is phosphorylated by Src at Y337 and Y347 in the proline-rich region (oval). Phosphorylation of mAbp1 at Y347 is required for podosome rosette formation and the inhibition of invasive migration. Y347 might be the crucial residue that mediates maturation of podosome dots to rosettes. Conversely, Src phosphorylation of both Y337 and Y347 impairs formation of podosome dots.We apologise for these errors. Summary Podosomes are dynamic actin-based structures that mediate adhesion to the extracellular matrix and localize matrix degradation to facilitate cell motility and invasion. Drebrin-like protein (DBNL), which is homologous to yeast mAbp1 and is therefore known as mammalian actin-binding protein 1 (mAbp1), has been implicated in receptor-mediated endocytosis, vesicle recycling and dorsal ruffle formation. However, it is not known whether mAbp1 regulates podosome formation or cell invasion. In this study, we found that mAbp1 localizes to podosomes and is necessary for the formation of podosome rosettes in Src-transformed fibroblasts. Despite their structural similarity, mAbp1 and cortactin play distinct roles in podosome regulation. Cortactin was necessary for the formation of podosome dots, whereas mAbp1 was necessary for the formation of organized podosome rosettes in Src-transformed cells. We identified specific Src phosphorylation sites, Tyr337 and Tyr347 of mAbp1, which mediate the formation of podosome rosettes and degradation of the ECM. In contrast to dorsal ruffles, the interaction of mAbp1 with WASP-interacting protein (WIP) was not necessary for the formation of podosome rosettes. Finally, we showed that depletion of mAbp1 increased invasive cell migration, suggesting that mAbp1 differentially regulates matrix degradation and cell invasion. Collectively, our findings identify a role for mAbp1 in podosome rosette formation and cell invasion downstream of Src.

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“…With lifetimes between 2-12 min, podosomes are very dynamic and continuously change size, shape, and composition~Destaing et al, 2003;Evans et al, 2003!. They have initially been identified in Src-transformed fibroblasts, and although previously thought to be restricted to only a few cell types, they have now been observed in smooth muscle cells, activated endothelial cells, and cells of the myeloid lineage such as osteoclasts, macrophages, and dendritic cells DCs!~Murphy & Courtneidge, 2011!. More recently, podosome-associated structures named invadopodia have been found on the ventral membranes of tumor cells where they are thought to play a central role in tumor metastasis Blouw et al, 2008;Mukhopadhyay et al, 2009!. Most of our current understanding of podosome formation, turnover, and distribution is based on studies that exploit conventional and confocal microscopy techniques. Although these techniques are potentially quantitative, largescale image analysis is required to obtain enough statistical power to be able to detect subtle and transient variations in podosome composition.…”

Section: Introductionmentioning

confidence: 99%

Automated Podosome Identification and Characterization in Fluorescence Microscopy Images

et al. 2013

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Podosomes are cellular adhesion structures involved in matrix degradation and invasion that comprise an actin core and a ring of cytoskeletal adaptor proteins. They are most often identified by staining with phalloidin, which binds F-actin and therefore visualizes the core. However, not only podosomes, but also many other cytoskeletal structures contain actin, which makes podosome segmentation by automated image processing difficult. Here, we have developed a quantitative image analysis algorithm that is optimized to identify podosome cores within a typical sample stained with phalloidin. By sequential local and global thresholding, our analysis identifies up to 76% of podosome cores excluding other F-actin-based structures. Based on the overlap in podosome identifications and quantification of podosome numbers, our algorithm performs equally well compared to three experts. Using our algorithm we show effects of actin polymerization and myosin II inhibition on the actin intensity in both podosome core and associated actin network. Furthermore, by expanding the core segmentations, we reveal a previously unappreciated differential distribution of cytoskeletal adaptor proteins within the podosome ring. These applications illustrate that our algorithm is a valuable tool for rapid and accurate large-scale analysis of podosomes to increase our understanding of these characteristic adhesion structures.

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p53 Suppresses Src-Induced Podosome and Rosette Formation and Cellular Invasiveness through the Upregulation of Caldesmon

Cited by 68 publications

References 61 publications

Sox4-mediated caldesmon expression facilitates skeletal myoblast differentiation

Sox4-mediated caldesmon expression facilitates skeletal myoblast differentiation

Src-mediated phosphorylation of mammalian Abp1 (DBNL) regulates podosome rosette formation in transformed fibroblasts

Automated Podosome Identification and Characterization in Fluorescence Microscopy Images

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