Foot and mouth: podosomes, invadopodia and circular dorsal ruffles

Buccione, Roberto; Orth, James D.; McNiven, Mark A.

doi:10.1038/nrm1436

Cited by 539 publications

(713 citation statements)

References 97 publications

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“…Focal adhesion kinase-related non-kinase inhibits focal adhesion kinase tyrosine phosphorylation and breast carcinoma cell invasion through Matrigel Tumor cell invasion is facilitated via cell protrusions called invadopodia that are sites of b1 integrin clustering, actin filament assembly and protease secretion (Buccione et al, 2004). As FAK facilitates invadopodia formation by v-Src (Hauck et al, 2001;Hsia et al, 2003), we investigated the localization and activity of FAK within murine 4T1 breast carcinoma cells (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Lim

et al. 2006

Oncogene

105

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Expression of focal adhesion kinase (FAK) is elevated in malignant breast cancer, yet the role of intrinsic FAK activity in promoting tumor progression remains undefined. Here, we have inhibited FAK activity or expression in murine 4T1 breast carcinoma cells via dominantnegative focal adhesion kinase-related non-kinase (FRNK) or anti-FAK short hairpin RNA (shRNA) expression, respectively. Neither FRNK nor FAK shRNA (B80% reduced FAK levels) affected 4T1 proliferation in culture, whereas reduced FAK activity or expression blocked 4T1 cell invasion through Matrigel and resulted in 2-3-fold lower urokinase plasminogen activator (uPA) expression. Control 4T1 cells implanted into mammary fat pads of BALB/c mice exhibited spontaneous metastasis to the lungs, to the peritoneal cavity, and resulted in 90% lethality within 21 days. Whereas FAK shRNAexpressing 4T1 cells formed tumors in mice with low levels of apoptosis, when mammary-injected, these cells did not exhibit lung metastasis after 21 days and caused only 40% lethality up to 60 days. Transient re-expression of wildtype but not kinase-dead FAK in 4T1 FAK shRNA cells promoted uPA production and mammary to lung metastasis within 7 days. In fact, stable human uPA overexpression in 4T1 FAK shRNA cells promoted Matrigel invasion and lung metastasis equal to 4T1 controls. Conversely, treatment with plasminogen activator inhibitor-1 or neutralizing antibody to uPA blocked Matrigel invasion of 4T1 control cells. These studies provide the first direct proof that FAK catalytic activity can facilitate metastatic breast cancer progression by regulating uPA expression.

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Section: Resultsmentioning

confidence: 99%

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Lim

et al. 2006

Oncogene

105

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“…Efficient cell migration requires a profound cytoskeleton re-organization and the formation protrusive structures termed lamellipodia, filopodia, invadopodia and podosomes 26 . Cytoskeletal staining with rhodamine-phalloidin showed that SMCs PCSK9 +/+ respond to PDGF-BB stimulation by acquiring an elongated morphology and by inducing lamellipodia formation ( Figure 6C).…”

Section: Effect Of Pcsk9 On Smc Migrationmentioning

confidence: 99%

PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement

et al. 2016

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Proprotein convertase subtilisin kexin type 9 (PCSK9) is a keyregulator of hepatic low-density lipoprotein-receptor (LDLR). PCSK9 is expressed in cultured smooth muscle cells (SMCs) and co-localizes with SMCs in human carotid atherosclerotic plaques. The present study aimed at comparing the neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in PCSK9 knock-out (PCSK9-/-) and wild type (WT) littermate (PCSK9+/+) mice. Collared carotids of the PCSK9-/-mice showed less intimal thickening compared to WT mice (p<0.05), a decreased intimal media ratio (p<0.02) and tendency to higher lumen area. When compared with PCSK9-/-, carotid lesions of WT mice had a higher content of SMCs (p<0.05) and collagen (p<0.05). No difference in macrophage content was detected between the two groups. SMCs freshly isolated from PCSK9-/-, when compared to PCSK9+/+ cells, showed higher levels of the contractile markers α-smooth muscle actin (α-SMA; 2.24±0.36 fold; p<0.01) and myosin heavy chain II (MHC-II; 8.65±1.55 fold; p<0.01), and decreased levels of synthetic markers caldesmon (-54±14%; p<0.01). PCSK9-/-cells also showed in response to platelet-derived growth factor-BB (PDGF-BB) a slower proliferation rate, and impaired migratory capacity and G1/S progression of the cell cycle. The reconstitution of PCSK9 expression, by retroviral infection of PCSK9-/-SMCs, led to a downregulation of α-SMA (-56±2%; p<0.01) and significant induction of caldesmon (1.46±0.3 fold; p<0.05). Proliferation rate of SMCs PCSK9-/-was significantly lower compared to PCSK9 reconstituted cells. Taken together, the present results suggest that by sustaining SMC synthetic phenotype, proliferation and migration PCSK9 may play a pro-atherogenic role in the arterial wall. HighlightsIn response to perivascular manipulation, the neointimal formation is reduced in PCSK9 -/-mice PCSK9 directly regulates smooth muscle cell differentiation, proliferation and migrationThe reconstitution of PCSK9 expression in SMCs PCSK9 -/-determines a switch towards a synthetic phenotype and rescue the impaired proliferation and migration capacities of SMCs PCSK9 -/-SMCs PCSK9 -/-respond less efficiently to the proliferative and chemotactic action of PDGF-BB 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractProprotein convertase subtilisin kexin type 9 (PCSK9) is a key-regulator of hepatic low-density lipoprotein-receptor (LDLR). PCSK9 is expressed in cultured smooth muscle cells (SMCs) and colocalizes with SMCs in human carotid atherosclerotic plaques. The present study aimed at comparing the neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in PCSK9 knock-out (PCSK9 -/-) and wild type (WT) littermate (PCSK9 +/+ ) mice. Collared carotids of the PCSK9 -/-mice showed less intimal thickening compared...

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“…Podosomes are typically formed in monocytic cells (monocytes, macrophages, dendritic cells and osteoclasts), endothelial cells and smooth muscle cells, whereas invadopodia are mostly found in cancer cells (Buccione et al, 2004;Linder and Kopp, 2005;Ayala et al, 2006;Gimona and Buccione, 2006;Weaver, 2006;Linder, 2007). Invadosomes in fibroblasts that have been transformed with tyrosine kinases such as Src show features of both podosomes and invadopodia, and their exact identity is currently unclear.…”

Section: Open Questions In Invadosome Biologymentioning

confidence: 99%

“…However, they are most likely to involve microtubuledependent trafficking of vesicles from the Golgi. Indeed, the Golgi is always observed in close proximity to invadopodia (Buccione et al, 2004;Ayala et al, 2006), and parts of the machinery for vesicle docking and fusion, such as the v-SNARE VAMP7 (Steffen et al, 2008) or the exocyst complex (Sakurai-Yageta et al, 2008), are required for MT1-MMP accumulation at invadopodia. In addition, MMP recruitment at invadosomes seems to involve parts of the actin cytoskeleton, most notably cortactin .…”

Section: Matrix Degradationmentioning

confidence: 99%