RAB7 Controls Melanoma Progression by Exploiting a Lineage-Specific Wiring of the Endolysosomal Pathway

Alonso-Curbelo, Direna; Riveiro-Falkenbach, Erica; Pérez-Guijarro, Eva; Cifdaloz, Metehan; Karras, Panagiotis; Osterloh, Lisa; Megı́as, Diego; Cañón, Estela; Calvo, Tonantzin G.; Olmeda, David; Gómez‐López, Gonzalo; Graña, Osvaldo; Lobo, Víctor J. Sánchez-Arévalo; Pisano, David G.; Wang, Hao Wei; Ortiz‐Romero, Pablo L.; Tormo, Damià; Hoek, Keith S.; Rodríguez‐Peralto, José Luis; Joyce, Johanna A.; Soengas, Marı́a S.

doi:10.1016/j.ccr.2014.04.030

Cited by 94 publications

(138 citation statements)

References 49 publications

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“…S3). Although this small GTPase is not itself considered a CLEAR network lysosomal gene, Rab7 has been recently shown to play a key role in the regulation of melanoma proliferation by exploiting a lineage-specific endolysosomal pathway wiring (32).…”

Section: Mitf Expression Levels Correlate With Many Lysosomal Genes Inmentioning

confidence: 99%

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

Ploper

Taelman

Robert³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

204

217

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Canonical Wnt signaling plays an important role in development and disease, regulating transcription of target genes and stabilizing many proteins phosphorylated by glycogen synthase kinase 3 (GSK3). We observed that the MiT family of transcription factors, which includes the melanoma oncogene MITF (micropthalmiaassociated transcription factor) and the lysosomal master regulator TFEB, had the highest phylogenetic conservation of three consecutive putative GSK3 phosphorylation sites in animal proteomes. This finding prompted us to examine the relationship between MITF, endolysosomal biogenesis, and Wnt signaling. Here we report that MITF expression levels correlated with the expression of a large subset of lysosomal genes in melanoma cell lines. MITF expression in the tetracycline-inducible C32 melanoma model caused a marked increase in vesicular structures, and increased expression of late endosomal proteins, such as Rab7, LAMP1, and CD63. These late endosomes were not functional lysosomes as they were less active in proteolysis, yet were able to concentrate Axin1, phospho-LRP6, phospho-β-catenin, and GSK3 in the presence of Wnt ligands. This relocalization significantly enhanced Wnt signaling by increasing the number of multivesicular bodies into which the Wnt signalosome/ destruction complex becomes localized upon Wnt signaling. We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. MITF stabilization caused an increase in multivesicular body biosynthesis, which in turn increased Wnt signaling, generating a positive-feedback loop that may function during the proliferative stages of melanoma. The results underscore the importance of misregulated endolysosomal biogenesis in Wnt signaling and cancer.MITF | Wnt-STOP | lysosome | melanoma | multivesicular body

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Section: Mitf Expression Levels Correlate With Many Lysosomal Genes Inmentioning

confidence: 99%

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

Ploper

Taelman

Robert³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

204

217

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“…A recent study found that melanomas rely on lysosomal function more than other cancers [66]. Interestingly, the related MiT transcription factors TFEB and TFE3, master lysosomal regulators, can Wnt ligand binding, the destruction complex that phosphorylates and targets ␤-Catenin for proteasomal degradation is recruited to the LRP6 receptor complex, which is endocytosed and subsequently sequestered inside intraluminal vesicles of multivesicular bodies (MVBs).…”

Section: The Mit Family In Cancermentioning

confidence: 99%

“…Among all cancers, melanomas rely on the endolysosomal pathway for growth more strongly than others, and lysosomal genes (plus lysosomal-associated genes such as Rab7) are more highly expressed in melanomas compared to other tumors [66]. Rab7, a small GTPase which has pivotal roles in lysosomal biogenesis and the degradation of lysosomal-associated vesicles [70][71][72], has been recently shown to be an early melanoma driver capable of rewiring the endolysosomal pathway in a lineage-specific fashion [66].…”

Section: Lysosomes and Autophagosomes In Melanomasmentioning

confidence: 99%

“…In addition, GSK3 inhibitors might enhance the effects of CQ on tumors highly dependent on endolysosomal activity, such as is the case in melanomas [66]. Inhibiting GSK3 activity with small molecules may be considered a double-edged sword as it could stimulate malignant transformation and cancer growth by activating Wnt/␤-Catenin signaling or by stabilizing oncogenes regulated by Wnt/STOP such as c-Jun and c-Myc [6,11].…”

Section: Pharmacological Approachesmentioning

confidence: 99%

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The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Ploper

Robertis

2015

Pharmacological Research

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a b s t r a c tCanonical Wnt signaling influences cellular fate and proliferation through inhibition of Glycogen Synthase Kinase (GSK3) and the subsequent stabilization of its many substrates, most notably ␤-Catenin, a transcriptional co-activator. MITF, a melanoma oncogene member of the microphthalmia family of transcription factors (MiT), was recently found to contain novel GSK3 phosphorylation sites and to be stabilized by Wnt. Other MiT members, TFEB and TFE3, are known to play important roles in cellular clearance pathways by transcriptionally regulating the biogenesis of lysosomes and autophagosomes via activation of CLEAR elements in gene promoters of target genes. Recent studies suggest that MITF can also upregulate many lysosomal genes. MiT family members are dysregulated in cancer and are considered oncogenes, but the underlying oncogenic mechanisms remain unclear. Here we review the role of MiT members, including MITF, in lysosomal biogenesis, and how cancers overexpressing MITF, TFEB or TFE3 could rewire the lysosomal pathway, inhibit cellular senescence, and activate Wnt signaling by increasing sequestration of negative regulators of Wnt signaling in multivesicular bodies (MVBs). Microarray studies suggest that MITF expression inhibits macroautophagy. In melanoma the MITF-driven increase in MVBs generates a positive feedback loop between MITF, Wnt, and MVBs.

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“…119,120 Caswell and colleagues established that Rab25 interaction with a5b1 integrin was essential in ovarian epithelial tumor cell invasion into a 3-dimensional fibronectin-enriched ECM and may additionally regulate MMP-dependent regulation. 117,121 Rab coupling protein (RCP), an effector of Rab11 and Rab25, acts as an oncogene as it promotes breast cancer transformation.…”

Section: 93mentioning

confidence: 99%

The role of endocytic Rab GTPases in regulation of growth factor signaling and the migration and invasion of tumor cells

Porther

Barbieri

2015

Small GTPases

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Metastasis is characterized pathologically by uncontrolled cell invasion, proliferation, migration and angiogenesis. It is a multistep process that encompasses the modulation of membrane permeability and invasion, cell spreading, cell migration and proliferation of the extracellular matrix, increase in cell adhesion molecules and interaction, decrease in cell attachment and induced survival signals and propagation of nutrient supplies (blood vessels). In cancer, a solid tumor cannot expand and spread without a series of synchronized events. Changes in cell adhesion receptor molecules (e.g., integrins, cadherin-catenins) and protease expressions have been linked to tumor invasion and metastasis. It has also been determined that ligand-growth factor receptor interactions have been associated with cancer development and metastasis via the endocytic pathway. Specifically, growth factors, which include IGF-1 and IGF-2 therapy, have been associated with most if not all of the features of metastasis. In this review, we will revisit some of the key findings on perhaps one of the most important hallmarks of cancer metastasis: cell migration and cell invasion and the role of the endocytic pathway in mediating this phenomenon

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RAB7 Controls Melanoma Progression by Exploiting a Lineage-Specific Wiring of the Endolysosomal Pathway

Cited by 94 publications

References 49 publications

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

The role of endocytic Rab GTPases in regulation of growth factor signaling and the migration and invasion of tumor cells

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