Rab7a is an enhancer of TPC2 activity regulating melanoma progression through modulation of the GSK3β/β-Catenin/MITF-axis.

Autor: Abrahamian C; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany.; Department of Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany., Tang R; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Deutsch R; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Ouologuem L; Department of Pharmacy, Ludwig-Maximilians-University, Munich, Germany., Weiden EM; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Kudrina V; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Blenninger J; Department of Pharmacy, Ludwig-Maximilians-University, Munich, Germany., Rilling J; Department of Pharmacy, Ludwig-Maximilians-University, Munich, Germany., Feldmann C; Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Kuss S; Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Stepanov Y; Laboratory for Functional Genome Analysis LAFUGA, Gene Center, Ludwig-Maximilians-University, Munich, Germany., Rosato AS; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Calvo GT; Melanoma Laboratory, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Research Centre), Madrid, Spain., Soengas MS; Melanoma Laboratory, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Research Centre), Madrid, Spain., Mayr D; Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Fröhlich T; Laboratory for Functional Genome Analysis LAFUGA, Gene Center, Ludwig-Maximilians-University, Munich, Germany., Gudermann T; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Biel M; Department of Pharmacy, Ludwig-Maximilians-University, Munich, Germany., Wahl-Schott C; Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany., Chen CC; Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan., Bartel K; Department of Pharmacy, Ludwig-Maximilians-University, Munich, Germany. karin.bartel@cup.uni-muenchen.de., Grimm C; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany. christian.grimm@med.uni-muenchen.de.; Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Munich/Frankfurt, Germany. christian.grimm@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 19; Vol. 15 (1), pp. 10008. Date of Electronic Publication: 2024 Nov 19.
DOI: 10.1038/s41467-024-54324-9
Abstrakt: Melanoma arising from pigment-producing melanocytes is the deadliest form of skin cancer. Extensive ultraviolet light exposure is a major cause of melanoma and individuals with low levels of melanin are at particular risk. Humans carrying gain-of-function polymorphisms in the melanosomal/endolysosomal two-pore cation channel TPC2 present with hypopigmentation, blond hair, and albinism. Loss of TPC2 is associated with decreased cancer/melanoma proliferation, migration, invasion, tumor growth and metastasis formation, and TPC2 depleted melanoma cells show increased levels of melanin. How TPC2 activity is controlled in melanoma and the downstream molecular effects of TPC2 activation on melanoma development remain largely elusive. Here we show that the small GTPase Rab7a strongly enhances the activity of TPC2 and that effects of TPC2 on melanoma hallmarks, in vitro and in vivo strongly depend on the presence of Rab7a, which controls TPC2 activity to modulate GSK3β, β-Catenin, and MITF, a major regulator of melanoma development and progression.
Competing Interests: Competing interests The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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