Ephexin3/ARHGEF5 Together with Cell Migration Signaling Partners within the Tumor Microenvironment Define Prognostic Transcriptional Signatures in Multiple Cancer Types
Cancer cell migration involves a repertoire of signaling proteins that lead cytoskeleton reorganization as a critical step in metastatic dissemination. RhoGEFs are multidomain effectors that integrate signaling inputs to activate the molecular switches that orchestrate actin cytoskeleton reorganizat...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/22/16427 |
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| author | Dante Gustavo Juan-Guadarrama Yarely Mabell Beltrán-Navarro Guadalupe Reyes-Cruz José Vázquez-Prado |
| author_facet | Dante Gustavo Juan-Guadarrama Yarely Mabell Beltrán-Navarro Guadalupe Reyes-Cruz José Vázquez-Prado |
| author_sort | Dante Gustavo Juan-Guadarrama |
| collection | DOAJ |
| description | Cancer cell migration involves a repertoire of signaling proteins that lead cytoskeleton reorganization as a critical step in metastatic dissemination. RhoGEFs are multidomain effectors that integrate signaling inputs to activate the molecular switches that orchestrate actin cytoskeleton reorganization. Ephexins, a group of five RhoGEFs, play oncogenic roles in invasive and metastatic cancer, leading to a mechanistic hypothesis about their function as signaling nodes assembling functional complexes that guide cancer cell migration. To identify clinically significant Ephexin signaling partners, we applied three systematic data mining strategies, based on the screening of essential Ephexins in multiple cancer cell lines and the identification of coexpressed signaling partners in the TCGA cancer patient datasets. Based on the domain architecture of encoded proteins and gene ontology criteria, we selected Ephexin signaling partners with a role in cytoskeletal reorganization and cell migration. We focused on Ephexin3/ARHGEF5, identified as an essential gene in multiple cancer cell types. Based on significant coexpression data and coessentiality, the signaling repertoire that accompanies Ephexin3 corresponded to three groups: pan-cancer, cancer-specific and coessential. To further select the Ephexin3 signaling partners likely to be relevant in clinical settings, we first identified those whose high expression was statistical linked to shorter patient survival. The resulting Ephexin3 transcriptional signatures represent significant accumulated risk, predictive of shorter survival, in 17 cancer types, including PAAD, LUAD, LGG, OSC, AML, KIRC, THYM, BLCA, LIHC and UCEC. The signaling landscape that accompanies Ephexin3 in various cancer types included the tyrosine kinase receptor <i>MET</i> and the tyrosine phosphatase receptor <i>PTPRF</i>, the serine/threonine kinases <i>MARK2</i> and <i>PAK6</i>, the Rho GTPases <i>RHOD</i>, <i>RHOF</i> and <i>RAC1</i>, and the cytoskeletal regulator <i>DIAHP1</i>. Our findings set the basis to further explore the role of Ephexin3/ARHGEF5 as an essential effector and signaling hub in cancer cell migration. |
| first_indexed | 2024-03-09T16:44:40Z |
| format | Article |
| id | doaj.art-1a0f36cd5a2747419945a73c8e3a1d4b |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:44:40Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1a0f36cd5a2747419945a73c8e3a1d4b2023-11-24T14:47:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124221642710.3390/ijms242216427Ephexin3/ARHGEF5 Together with Cell Migration Signaling Partners within the Tumor Microenvironment Define Prognostic Transcriptional Signatures in Multiple Cancer TypesDante Gustavo Juan-Guadarrama0Yarely Mabell Beltrán-Navarro1Guadalupe Reyes-Cruz2José Vázquez-Prado3Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, Mexico City 07360, MexicoDepartment of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, Mexico City 07360, MexicoDepartment of Cell Biology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, Mexico City 07360, MexicoDepartment of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, Mexico City 07360, MexicoCancer cell migration involves a repertoire of signaling proteins that lead cytoskeleton reorganization as a critical step in metastatic dissemination. RhoGEFs are multidomain effectors that integrate signaling inputs to activate the molecular switches that orchestrate actin cytoskeleton reorganization. Ephexins, a group of five RhoGEFs, play oncogenic roles in invasive and metastatic cancer, leading to a mechanistic hypothesis about their function as signaling nodes assembling functional complexes that guide cancer cell migration. To identify clinically significant Ephexin signaling partners, we applied three systematic data mining strategies, based on the screening of essential Ephexins in multiple cancer cell lines and the identification of coexpressed signaling partners in the TCGA cancer patient datasets. Based on the domain architecture of encoded proteins and gene ontology criteria, we selected Ephexin signaling partners with a role in cytoskeletal reorganization and cell migration. We focused on Ephexin3/ARHGEF5, identified as an essential gene in multiple cancer cell types. Based on significant coexpression data and coessentiality, the signaling repertoire that accompanies Ephexin3 corresponded to three groups: pan-cancer, cancer-specific and coessential. To further select the Ephexin3 signaling partners likely to be relevant in clinical settings, we first identified those whose high expression was statistical linked to shorter patient survival. The resulting Ephexin3 transcriptional signatures represent significant accumulated risk, predictive of shorter survival, in 17 cancer types, including PAAD, LUAD, LGG, OSC, AML, KIRC, THYM, BLCA, LIHC and UCEC. The signaling landscape that accompanies Ephexin3 in various cancer types included the tyrosine kinase receptor <i>MET</i> and the tyrosine phosphatase receptor <i>PTPRF</i>, the serine/threonine kinases <i>MARK2</i> and <i>PAK6</i>, the Rho GTPases <i>RHOD</i>, <i>RHOF</i> and <i>RAC1</i>, and the cytoskeletal regulator <i>DIAHP1</i>. Our findings set the basis to further explore the role of Ephexin3/ARHGEF5 as an essential effector and signaling hub in cancer cell migration.https://www.mdpi.com/1422-0067/24/22/16427Ephexin3Rho guanine nucleotide exchange factor (RhoGEF)cancer signaling signaturecancer datasets miningTCGADepMap |
| spellingShingle | Dante Gustavo Juan-Guadarrama Yarely Mabell Beltrán-Navarro Guadalupe Reyes-Cruz José Vázquez-Prado Ephexin3/ARHGEF5 Together with Cell Migration Signaling Partners within the Tumor Microenvironment Define Prognostic Transcriptional Signatures in Multiple Cancer Types International Journal of Molecular Sciences Ephexin3 Rho guanine nucleotide exchange factor (RhoGEF) cancer signaling signature cancer datasets mining TCGA DepMap |
| title | Ephexin3/ARHGEF5 Together with Cell Migration Signaling Partners within the Tumor Microenvironment Define Prognostic Transcriptional Signatures in Multiple Cancer Types |
| title_full | Ephexin3/ARHGEF5 Together with Cell Migration Signaling Partners within the Tumor Microenvironment Define Prognostic Transcriptional Signatures in Multiple Cancer Types |
| title_fullStr | Ephexin3/ARHGEF5 Together with Cell Migration Signaling Partners within the Tumor Microenvironment Define Prognostic Transcriptional Signatures in Multiple Cancer Types |
| title_full_unstemmed | Ephexin3/ARHGEF5 Together with Cell Migration Signaling Partners within the Tumor Microenvironment Define Prognostic Transcriptional Signatures in Multiple Cancer Types |
| title_short | Ephexin3/ARHGEF5 Together with Cell Migration Signaling Partners within the Tumor Microenvironment Define Prognostic Transcriptional Signatures in Multiple Cancer Types |
| title_sort | ephexin3 arhgef5 together with cell migration signaling partners within the tumor microenvironment define prognostic transcriptional signatures in multiple cancer types |
| topic | Ephexin3 Rho guanine nucleotide exchange factor (RhoGEF) cancer signaling signature cancer datasets mining TCGA DepMap |
| url | https://www.mdpi.com/1422-0067/24/22/16427 |
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