Rab7a is an enhancer of TPC2 activity regulating melanoma progression through modulation of the GSK3β/β-Catenin/MITF-axis
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.
Authors
- Eva-Maria Weiden (ORCID: https://orcid.org/0000-0001-9582-4448)
- Anna Scotto Rosato (ORCID: https://orcid.org/0000-0002-1358-299X)
- Cheng‐Chang Chen (ORCID: https://orcid.org/0000-0003-1282-4026)
- Thomas Fröhlich (ORCID: https://orcid.org/0000-0002-4709-3211)
- Christian Grimm (ORCID: https://orcid.org/0000-0002-0177-5559)
- Marı́a S. Soengas (ORCID: https://orcid.org/0000-0003-0612-6299)
- Colin Feldmann
- Karin Bartel (ORCID: https://orcid.org/0000-0002-6634-547X)
- Solveig Kuss (ORCID: https://orcid.org/0000-0002-2363-8475)
- Carla Abrahamian (ORCID: https://orcid.org/0000-0002-0425-8004)
- Guadalupe T. Calvo
- Veronika Kudrina (ORCID: https://orcid.org/0000-0002-3762-8673)
- Youli K. Stepanov (ORCID: https://orcid.org/0000-0001-5534-8539)
- Thomas Gudermann (ORCID: https://orcid.org/0000-0002-0323-7965)
- Christian Wahl‐Schott (ORCID: https://orcid.org/0000-0002-7514-2367)
- Rachel Tang (ORCID: https://orcid.org/0000-0003-1514-2100)
- Julia Rilling
- Martin Biel (ORCID: https://orcid.org/0000-0002-9974-3052)
- Lina Ouologuem (ORCID: https://orcid.org/0009-0007-4648-3641)
- Julia Blenninger (ORCID: https://orcid.org/0009-0004-9442-8055)
- Doris Mayr
- Rebecca Deutsch
Institutions
- National Taiwan University (TW)
- Spanish National Cancer Research Centre (ES)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- National Taiwan University Hospital (TW)
- Deutsches Herzzentrum München (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1038/s41467-024-54324-9
- Citations
- 17
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 6.84
Funders
- Deutsche Forschungsgemeinschaft