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

Carla Abrahamian, Rachel Tang, Rebecca Deutsch, Lina Ouologuem, Eva-Maria Weiden, Veronika Kudrina, Julia Blenninger, Julia Rilling, Colin Feldmann, Solveig Kuss, Youli Stepanov, Anna Scotto Rosato, Guadalupe T. Calvo, Maria S. Soengas, Doris Mayr, Thomas Fröhlich, Thomas Gudermann, Martin Biel, Christian Wahl-Schott, Cheng-Chang Chen, Karin Bartel () and Christian Grimm ()
Additional contact information
Carla Abrahamian: Ludwig-Maximilians-University
Rachel Tang: Ludwig-Maximilians-University
Rebecca Deutsch: Ludwig-Maximilians-University
Lina Ouologuem: Ludwig-Maximilians-University
Eva-Maria Weiden: Ludwig-Maximilians-University
Veronika Kudrina: Ludwig-Maximilians-University
Julia Blenninger: Ludwig-Maximilians-University
Julia Rilling: Ludwig-Maximilians-University
Colin Feldmann: Ludwig-Maximilians-University
Solveig Kuss: Ludwig-Maximilians-University
Youli Stepanov: Ludwig-Maximilians-University
Anna Scotto Rosato: Ludwig-Maximilians-University
Guadalupe T. Calvo: Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Research Centre)
Maria S. Soengas: Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Research Centre)
Doris Mayr: Ludwig-Maximilians-University
Thomas Fröhlich: Ludwig-Maximilians-University
Thomas Gudermann: Ludwig-Maximilians-University
Martin Biel: Ludwig-Maximilians-University
Christian Wahl-Schott: Ludwig-Maximilians-University
Cheng-Chang Chen: National Taiwan University
Karin Bartel: Ludwig-Maximilians-University
Christian Grimm: Ludwig-Maximilians-University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54324-9

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