Cortactin: coupling membrane dynamics to cortical actin assembly

Weed, Scott A.; Parsons, J. Thomas

doi:10.1038/sj.onc.1204783

Cited by 380 publications

(411 citation statements)

References 217 publications

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“…In contrast, two extracellular signal-regulated kinase (ERK) sites located at Ser-405 and Ser-418 sites, and ERK phosphorylation enhances cortactin binding and activation of N-WASP (Huang et al, 1998;Campbell et al, 1999;Weed and Parsons, 2001;Martinez-Quiles et al, 2004). Recent studies using mass spectrometry have identified 17 new sites of phosphorylation (12 serine, 4 threonine and 1 tyrosine), suggesting that cortactin is heavily phosphorylated in vivo (Martin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Deacetylation of cortactin by SIRT1 promotes cell migration

et al. 2008

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Cortactin binds F-actin and promotes cell migration. We showed earlier that cortactin is acetylated. Here, we identify SIRT1 (a class III histone deacetylase) as a cortactin deacetylase and p300 as a cortactin acetylase. We show that SIRT1 deacetylates cortactin in vivo and in vitro and that the SIRT1 inhibitor EX-527 increases amounts of acetylated cortactin in ovarian cancer cells. We also show that p300 acetylates cortactin in vivo and that cells lacking or depleted of p300 express lessacetylated cortactin than do control cells. Deletion analysis mapped the SIRT1-binding domain of cortactin to its repeat region, which also binds F-actin. Mouse embryo fibroblasts (MEFs) lacking sir2a (the mouse homolog of SIRT1) migrated more slowly than did wildtype cells. The expression of SIRT1 in sir2a-null cells restored migratory capacity, as did expression of a deacetylation-mimetic mutant of cortactin. SIRT1 and cortactin were more abundant in breast tumor tissue than in their normal counterparts, whereas SIRT1 expression inversely correlates with the ratio of acetylation cortactin versus total cortactin. These data suggest that deacetylation of cortactin is associated with high levels of SIRT1 and tumorigenesis. Finally, breast and ovarian cancer cell lines expressing an acetylation mimetic mutant of cortactin are less motile than that of control cells, whereas cells expressing the deacetylation mimetic mutant of cortactin migrate faster than that of control cells in Transwell migration assays. In summary, our results suggest that cortactin is a novel substrate for SIRT1 and p300 and, for the first time, a possible role for SIRT1 in cell motility through deacetylation of cortactin.

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Section: Introductionmentioning

confidence: 99%

Deacetylation of cortactin by SIRT1 promotes cell migration

et al. 2008

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“…Cortactin, a regulator of ARP2/3-mediated actin polymerization, is known to contribute to tumour cell growth and cancer progression (Weed and Parsons, 2001). Downregulation of cortactin in cancer cell lines decreases the cellular motility and ability to migrate (Rothschild et al, 2006;van Rossum et al, 2006) whereas overexpression resulted in an increased invasive potential (van Rossum et al, 2003;Rothschild et al, 2006).…”

Section: Discussion Cortactin Predicts Poor Survival In Late Stage Lamentioning

confidence: 99%

Cortactin expression predicts poor survival in laryngeal carcinoma

et al. 2008

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Amplification of the 11q13 region is one of the most frequent aberrations in squamous cell carcinomas of the head and neck region (HNSCC). Amplification of 11q13 has been shown to correlate with the presence of lymph node metastases and decreased survival. The 11q13.3 amplicon carries numerous genes including cyclin D1 and cortactin. Recently, we reported that FADD becomes overexpressed upon amplification and that FADD protein expression predicts for lymph node positivity and disease-specific mortality. However, the gene within the 11q13.3 amplicon responsible for this correlation is yet to be identified. In this paper, we compared, using immunohistochemical analysis for cyclin D1, FADD and cortactin in a series of 106 laryngeal carcinomas which gene correlates best with lymph node metastases and increased disease-specific mortality. Univariate Cox regression analysis revealed that high expression of cyclin D1 (P ¼ 0.016), FADD (P ¼ 0.003) and cortactin (P ¼ 0.0006) predict for increased risk to disease-specific mortality. Multivariate Cox analysis revealed that only high cortactin expression correlates with disease-specific mortality independent of cyclin D1 and/or FADD. Of genes located in the 11q13 amplicon, cortactin expression is the best predictor for shorter diseasespecific survival in late stage laryngeal carcinomas. Current methods to predict the outcome of head and neck squamous cell carcinoma (HNSCC) patients mainly involve clinicopathological parameters such as tumour size, differentiation grade and presence of lymph node metastasis. Patients with laryngeal squamous cell carcinomas (LSCC) have not shown an increase in 5-year survival rates over the last 30 years (Almadori et al, 2005). Therefore, other parameters such as molecular markers that are able to more accurately predict the outcome of disease, are needed.A frequent molecular event in HNSCC is amplification of the 11q13 region (36%) (Schuuring, 1995;Freier et al, 2006). Amplification of this region in HNSCC has been associated with decreased survival (Akervall et al, 1995;Meredith et al, 1995), increased distant metastasis (Namazie et al, 2002) and lymph node metastasis (Chen et al, 2004;Hermsen et al, 2005;Xia et al, 2007). It is believed that amplification increases gene dosage and expression of genes within the amplified region (amplicon) (Albertson, 2006). Recently, we reported that the commonly amplified region is located at 11q13.3 and contains at least six genes (cyclin D1, TAOS1, FGF19, FADD, PPFIA1 and cortactin) that are overexpressed when amplified (Gibcus et al, 2007b). We concluded that the selection for tumour cells with the 11q13.3 amplicon during tumorigenesis could be based on the increased doses of one or more of these genes. We proposed FADD as a possible candidate for this selection, since FADD showed the best correlation between DNA amplification and increased expression (Gibcus et al, 2007b). Furthermore, FADD protein expression correlated with disease specific mortality (DSM) in a series of late stage laryngeal carcinom...

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“…The p130Cas-CRK complex is reported to trigger actin polymerization by a Rac-independent mechanism [29]. Cortactin is an actin-associated scaffolding protein that binds and activates the actin-related protein (Arp) 2/3 complex, structures [39,40]. Cortactin and CRK cooperate to trigger actin polymerization during Shigella invasion of epithelial cells [41].…”

Section: Effect Of Decreasing Crkii Expression On Crkii-p130cas Signamentioning

confidence: 99%

Overexpression of CRKII increases migration and invasive potential in oral squamous cell carcinoma

et al. 2011

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CT10 regulator of kinase (CRK) was originally identified as an oncogene product of v-CRK in a CT10 chicken retrovirus system. Overexpression of CRKII has been reported in several human cancers. CRKII regulates cell migration, morphogenesis, invasion, phagocytosis, and survival; however, the underlying mechanisms are not well understood. In the present study, we evaluated the possibility of CRKII as an appropriate molecular target for cancer gene therapy. The expression of CRKII in 71 primary oral squamous cell carcinomas and 10 normal oral mucosal specimens was determined immunohistochemically, and the correlation of CRKII overexpression with clinicopathological factors was evaluated.Overexpression of CRKII was detected in 41 of 70 oral squamous cell carcinomas, the frequency being more significant than in normal oral mucosa. In addition, CRKII overexpression was more frequent in higher-grade cancers according to the T classification, N classification, and invasive pattern. Moreover, RNAi-mediated suppression of CRKII expression reduced the migration and invasion potential of an oral squamous cell carcinoma cell line, OSC20. Downregulation of CRKII expression also reduced the expression of Dock180, p130Cas, and Rac1, and the actin-associated scaffolding protein cortactin. These results indicate that the overexpression of CRKII is tightly associated with an aggressive phenotype of oral squamous cell carcinoma. Therefore, we propose that CRKII could be a potential molecular target of gene therapy by RNAi-targeting in oral squamous cell carcinoma. 4

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Cortactin: coupling membrane dynamics to cortical actin assembly

Cited by 380 publications

References 217 publications

Deacetylation of cortactin by SIRT1 promotes cell migration

Deacetylation of cortactin by SIRT1 promotes cell migration

Cortactin expression predicts poor survival in laryngeal carcinoma

Overexpression of CRKII increases migration and invasive potential in oral squamous cell carcinoma

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