Ezrin interacts with cortactin to form podosomal rosettes in pancreatic cancer cells

Kocher, Hemant M.; Sandle, J; Mirza, T.; Li, Ningfeng F.; Hart, Ian R.

doi:10.1136/gut.2008.159871

Cited by 53 publications

(55 citation statements)

References 38 publications

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“…S4B). Consistent with previous reports, live imaging analysis suggested that the podosome rosettes are formed by the maturation of pre-existing podosome dots (Kocher et al, 2009;Poincloux et al, 2005;Gavazzi et al, 1989), and this maturation was impaired in mAbp1-deficient cells (Fig. 2D,E and supplementary material Fig.…”

Section: Resultssupporting

confidence: 76%

“…In addition to dot-like podosomes, Srctransformed fibroblasts, some cancer cells, endothelial cells, and osteoclasts also form highly organized adhesive structures known as podosome rosettes. These organized structures mediate adhesion and migration of pancreatic cancer cells through the basal lamina (Kocher et al, 2009) and have also been implicated in mediating force transmission and mechanotransduction in a similar manner to focal adhesions (Collin et al, 2008). In addition, podosome rosettes in osteoclasts can mature into sealing rings that mediate degradation of the bone matrix (Teti et al, 1991;Destaing et al, 2003).…”

Section: Src-mediated Phosphorylation Of Mammalian Abp1 (Dbnl) Regulamentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 76%

Section: Src-mediated Phosphorylation Of Mammalian Abp1 (Dbnl) Regulamentioning

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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“…SKAP2-mediated macrophage invasion is considered as a combined effect through podosome formation and previously reported actin ruffles, and localization of SKAP2 in punctate structures associated with ruffles was also described (22). In addition to individual podosomes, podosome rosettes, which are organized structures of individual podosomes that mediate cell adhesion, were occasionally observed in RAW264.7 macrophages (29). As podosome rosettes were not detected in SKAP2-deficient RAW264.7 cells, SKAP2 may also be involved in the formation of these adhesive structures.…”

Section: Discussionmentioning

confidence: 99%

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

et al. 2016

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Tumor-associated macrophages (TAM) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulates within metastatic sites to promote the invasion and growth of tumor cells. Src kinase-associated phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages from various tumors, but its contribution to the tumor-promoting behavior of TAMs is unknown. Here, we report that SKAP2 regulates podosome formation in macrophages to promote tumor invasion and metastasis. SKAP2 physically interacted with Wiskott-Aldrich syndrome protein (WASP) and localized to podosomes, which were rarely observed in SKAP2-null macrophages. The invasion of peritoneal macrophages derived from SKAP2-null mice was significantly reduced compared with wild-type macrophages, but could be rescued by the restoration of functional SKAP2 containing an intact tyrosine phosphorylation site and the ability to interact with WASP. Furthermore, SKAP2-null mice inoculated with lung cancer cells exhibited markedly decreased lung metastases characterized by reduced macrophage infiltration compared with wild-type mice. Moreover, intravenously injected SKAP2-null macrophages failed to efficiently infiltrate established tumors and promote their growth. Taken together, these findings reveal a novel mechanism by which macrophages assemble the appropriate motile machinery to infiltrate tumors and promote disease progression, and implicate SKAP2 as an attractive candidate for therapeutically targeting TAMs. Cancer Res; 76(2); 358-69. Ó2015 AACR.

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“…Furthermore, ezrin expression is correlated with an early recurrence of hepatocellular carcinoma (22), invasion of pancreatic adenocarcinoma (23) and lymph node metastasis of prostate cancer (24) and nasopharyngeal carcinoma (25).…”

Section: Discussionmentioning

confidence: 99%

Ezrin expression and its phosphorylation in gastric carcinoma with lymphoid stroma and Epstein-Barr virus infection

Tobo

Hirahashi

Yao

et al. 2012

Molecular and Clinical Oncology

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Abstract. Gastric carcinoma with lymphoid stroma (GCLS) is a unique variant of gastric carcinoma that represents prominent lymphocytic infiltration and is correlated with Epstein-Barr virus (EBV) infection. Ezrin expression and activation are crucial in tumor metastasis and induce cell migration of EBV-related nasopharyngeal carcinomas. Using immunohistochemical methods, the expression of total and phosphorylated ezrin (p-ezrin), Thr567, was examined in 104 GCLS cases, including 78 EBV-positive and 26 EBV-negative cases, as well as 29 non-GCLS cases. Positive ezrin expression was detected to be at markedly higher levels in GCLS compared to non-GCLS (P<0.0001). Furthermore, ezrin expression was detected to be at higher levels in EBV-positive compared to EBV-negative GCLS (P=0.0294). High expression of p-ezrin in GCLS was associated with positive lymph node metastasis (P=0.0187). In summary, these results demonstrated that ezrin overexpression is correlated with the histologic characteristics of GCLS and EBV infection. Phosphorylation of ezrin may, therefore, contribute to lymph node metastasis in GCLS.

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Ezrin interacts with cortactin to form podosomal rosettes in pancreatic cancer cells

Abstract: Podosomes and their rosettes are driven by ezrin-cortactin interaction and this plays a role in pancreatic cancer invasion.

Cited by 53 publications

References 38 publications

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

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

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression

Ezrin expression and its phosphorylation in gastric carcinoma with lymphoid stroma and Epstein-Barr virus infection

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