Modeling ErbB2-p130Cas interaction to design new potential anticancer agents

Costamagna, Andrea; Sebastiano, Matteo Rossi; Natalini, Dora; Simoni, Maria-Grazia De; Valabrega, Giorgio; Defilippi, Paola; Visentin, Sonja; Ermondi, Giuseppe; Turco, Emilia; Cabodi, Sara

doi:10.1038/s41598-019-39510-w

Cited by 4 publications

(5 citation statements)

References 39 publications

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“…HER2-targeted therapies such as TZMB and pertuzumab have been recommended in combination with chemotherapy for HER2-overexpressing breast and gastric cancer patients [9] , [10] , but frequently emerging resistance has created a need for alternative strategies. Thus, instead of targeting already overexpressed HER2, several experimental attempts have been made to identify small molecules that transcriptionally inhibit HER2 expression [53] , [54] , [55] , [56] , [57] , [58] , but nothing has yet reached clinical trials. HER2 expression-related PPIs occur between various TFs and coactivators as follows: TFs are ELF3 [17] , [22] , activator protein-2 (AP-2) [39] , SP1 [40] , [41] , signal transducer and activator of transcription 3 (STAT3) [42] , Y-box binding protein-1 (YBX1 or YB1) [43] , and EGR2 [44] , [45] , and coactivators are MED23, CITED2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2) [44] , [45] , and Yin Yang 1 (YY1) [46] , [47] .…”

Section: Discussionmentioning

confidence: 99%

Interrupting specific hydrogen bonds between ELF3 and MED23 as an alternative drug resistance-free strategy for HER2-overexpressing cancers

Hwang

Park

et al. 2023

Journal of Advanced Research

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Section: Discussionmentioning

confidence: 99%

Interrupting specific hydrogen bonds between ELF3 and MED23 as an alternative drug resistance-free strategy for HER2-overexpressing cancers

Hwang

Park

et al. 2023

Journal of Advanced Research

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“…In addition to its signaling role in FAs, P130cas also plays an essential role in regulating cell proliferation and survival in cancer cells [ 17 , 40 ]. Silencing P130cas has been reported to reduce cell proliferation in breast cancer and ovarian carcinoma [ 42 , 43 ]. However, proliferation was not affected by reducing P130cas expression in oral carcinoma [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

P130cas-FAK interaction is essential for YAP-mediated radioresistance of non-small cell lung cancer

Zhang

Hou

et al. 2022

Cell Death Dis

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Based on the RNA-sequencing data, previous studies revealed that extracellular matrix receptor interaction and focal adhesion signaling pathways were enriched in radioresistant non-small cell lung cancer (NSCLC) cell lines. As the principal members of these signaling pathways, recent studies showed that FAK controlled YAP’s nuclear translocation and activation in response to mechanical activation. However, the underlying mechanisms are largely unknown. This study was designed to determine whether P130cas plays a role in FAK-YAP axis-mediated radioresistance. We found that P130cas promoted proliferation, altered the cell cycle profile, and enhanced tumor growth using cell lines and xenograft mouse models. After treating the cell lines and xenograft models with a single dose of 5 Gy irradiation, we observed that P130cas effectively induced radioresistance in vitro and in vivo. We confirmed that P130cas interacted with and promoted YAP stabilization, thereby facilitating YAP’s activation and nuclear translocation and downregulating the radiosensitivity of NSCLC. Our data also revealed that P130cas and FAK directly interacted with each other and worked together to regulate YAP’s activation and nuclear translocation. Furthermore, the present study identified that P130cas, FAK and YAP formed a triple complex to induce radioresistance. Using P130cas-ΔSH3, FAK- P712/715A mutant, YAP-ΔSH3bm and YAP-ΔWW mutant, our results showed that targeting P130cas-FAK interaction may be a more cost-effective way to overcome the YAP activation mediated radioresistance in NSCLC. Using the data of the public database and our clinical samples, the present study suggested that the expression of P130cas correlated with YAP expression and indicated a poor overall response rate of NSCLC patients who underwent radiation therapy. Overall, our study extends the knowledge of FAK-YAP interaction and provides new insight into understanding the underlying mechanisms to overcome the radioresistance of NSCLC.

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“…Their experimental validation was performed in vitro and in ErbB2-positive breast cancer cellular models. The results highlight that both compounds interfere with p130Cas/ErbB2 binding and significantly affect cell proliferation and sensitivity to Trastuzumab ( Costamagna et al, 2019 ). This study supports p130Cas/ErbB2 complex as a potential breast cancer target and shows the druggability of this protein-protein interaction (PPI) that might benefit from a more advanced optimization effort for therapeutic applications.…”

Section: P130 Crk-associated Substrate: Translational Applicationsmentioning

confidence: 99%

p130Cas/BCAR1 and p140Cap/SRCIN1 Adaptors: The Yin Yang in Breast Cancer?

Centonze

Natalini

Salemme

et al. 2021

Front. Cell Dev. Biol.

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p130Cas/BCAR1 is an adaptor protein devoid of any enzymatic or transcriptional activity, whose modular structure with various binding motifs, allows the formation of multi-protein signaling complexes. This results in the induction and/or maintenance of signaling pathways with pleiotropic effects on cell motility, cell adhesion, cytoskeleton remodeling, invasion, survival, and proliferation. Deregulation of p130Cas/BCAR1 adaptor protein has been extensively demonstrated in a variety of human cancers in which overexpression of p130Cas/BCAR1 correlates with increased malignancy. p140Cap (p130Cas associated protein), encoded by the SRCIN1 gene, has been discovered by affinity chromatography and mass spectrometry analysis of putative interactors of p130Cas. It came out that p140Cap associates with p130Cas not directly but through its interaction with the Src Kinase. p140Cap is highly expressed in neurons and to a lesser extent in epithelial tissues such as the mammary gland. Strikingly, in vivo and in vitro analysis identified its tumor suppressive role in breast cancer and in neuroblastoma, showing an inverse correlation between p140Cap expression in tumors and tumor progression. In this review, a synopsis of 15 years of research on the role of p130Cas/BCAR1 and p140Cap/SRCIN1 in breast cancer will be presented.

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Modeling ErbB2-p130Cas interaction to design new potential anticancer agents

Cited by 4 publications

References 39 publications

Interrupting specific hydrogen bonds between ELF3 and MED23 as an alternative drug resistance-free strategy for HER2-overexpressing cancers

Interrupting specific hydrogen bonds between ELF3 and MED23 as an alternative drug resistance-free strategy for HER2-overexpressing cancers

P130cas-FAK interaction is essential for YAP-mediated radioresistance of non-small cell lung cancer

p130Cas/BCAR1 and p140Cap/SRCIN1 Adaptors: The Yin Yang in Breast Cancer?

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