Dokument: New insights into the classification of the RAC1 P29S hotspot mutation in melanoma as an oncogene
| Titel: | New insights into the classification of the RAC1 P29S hotspot mutation in melanoma as an oncogene | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=71954 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20260120-121822-9 | |||||||
| Kollektion: | Publikationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Texte » Artikel, Aufsatz | |||||||
| Medientyp: | Text | |||||||
| Autoren: | Mirzaiebadizi, Amin [Autor] Ahmadian, Mohammad Reza [Autor] | |||||||
| Dateien: |
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| Beschreibung: | The RAC1P29S hotspot mutation, which is prevalent in melanoma, drives tumorigenesis by promoting the persistent activation of RAC1. This mutation enhances molecular interactions, and hyperactivates key signaling pathways, making RAC1P29S a promising target for cancer therapy. This study provides a comprehensive biochemical and cell-based characterization of RAC1P29S, as well as comparisons with wild-type RAC1 and the T17N and F28L mutants. The P29S substitution significantly impairs nucleotide binding while accelerating intrinsic nucleotide exchange. While it minimally affects regulation by guanosine dissociation inhibitor 1 (GDI1), RAC1P29S exhibits reduced activation via DBL family guanine nucleotide exchange factors (GEFs) but retains effective activation by dedicator of cytokinesis 2 (DOCK2). Importantly, the P29S mutation severely impairs GTPase-activating protein-stimulated GTP hydrolysis, which most likely contributes to RAC1P29S hyperactivation by prolonging its GTP-bound active form. This mutation displays a stronger binding affinity for the IQ motif-containing GTPase-activating protein 1 (IQGAP1) than for the p21-activated kinase 1 (PAK1), indicating altered effector interactions that modulate downstream signaling spatially. These biochemical findings are consistent with the fact that RAC1P29S predominantly adopts an active GTP-bound state under serum-starved conditions. IGR1 human melanoma cells harboring endogenous RAC1P29S exhibit persistent RAC1P29S•GTP accumulation, even without upstream GEF activation. Furthermore, the pharmacological inhibition of DOCK2 with CPYPP significantly reduces RAC1P29S activation in these cells, which confirms the pivotal role of DOCK2 in sustaining RAC1P29S-driven signaling. Overexpression of RAC1P29S activates key oncogenic pathways, including ERK1/2 and p38 MAPK, highlighting its role as a constitutively active driver mutation. Together, these results imply that targeting upstream regulators such as DOCK2 and downstream effectors, such as IQGAP1, could be effective therapeutic strategies for counteracting RAC1P29S-mediated melanoma progression and resistance to targeted therapies. | |||||||
| Rechtliche Vermerke: | Originalveröffentlichung:
Mirzaiebadizi, A., & Ahmadian, M. R. (2025). New insights into the classification of the RAC1 P29S hotspot mutation in melanoma as an oncogene. Cancer Gene Therapy, 32(12), 1341–1355. https://doi.org/10.1038/s41417-025-00965-x | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 20.01.2026 | |||||||
| Dateien geändert am: | 20.01.2026 |
