Fig. 8: Proposed mechanism of β-Catenin and MITF regulation in SK-MEL-5 WT and Rab7/TPC2 KO cells. | Nature Communications

Fig. 8: Proposed mechanism of β-Catenin and MITF regulation in SK-MEL-5 WT and Rab7/TPC2 KO cells.

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

Fig. 8

In WT cells, Rab7a upregulates activity of TPC2 which induces endolysosomal degradation of the GSK3β complex. Downregulation of GSK3β leads to decreased phosphorylation of β-Catenin, which then translocates in its dephosphorylated state to the nucleus and activates MITF transcription. The transcription factor MITF induces the transcription of various genes upregulating cell migration, invasion, proliferation and tumor growth. Furthermore, decreased GSK3β levels lead to decreased phosphorylation of MITF, hence less proteosomal degradation of MITF. When Rab7a or TPC2 is dysfunctional or knocked out, GSK3β phosphorylates β-Catenin and MITF promoting their proteosomal degradation, and blocking β-Catenin from translocation to the nucleus. Less MITF transcription leads to a decrease in migration, invasion, proliferation and tumor growth, suggesting that TPC2 GOF SNPs and high Rab7a expression may be risk factors for melanoma. “Created in BioRender. BioRender.com/c52w590”.

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