Abstract
UbiA prenyltransferase domain-containing protein 1 (UBIAD1) plays a key role in biosynthesis of vitamin K2 and coenzyme Q10 using geranylgeranyl diphosphate (GGPP). However, the mechanism by which UBIAD1 participates in tumorigenesis remains unknown. This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. In addition, GGPP was required to maintain the function of UBIAD1 in regulating the Ras/ERK signaling pathway. A Drosophila model was employed to confirm the function of UBIAD1/HEIX in vivo. The activation of Ras/ERK signaling at the plasma membrane induced melanotic masses in Drosophila larvae. Our study suggests that UBIAD1 serves as a tumor suppressor in cancer and tentatively reveals the underlying mechanism of melanotic mass formation in Drosophila.
Highlights
Ras proteins are essential components of the intracellular signaling cascades that regulate various fundamental cellular activities such as proliferation, apoptosis, differentiation, and senescence[1,2]
UbiA prenyltransferase domain-containing protein 1 (UBIAD1) downregulation has been shown to induce the activation of the Ras/MAPK signaling pathway[39], and UBIAD1 has inhibited the growth of bladder (Fig. 1a-c)[20] and prostate cancers[21]
An increase in p-ERK was prevented by the green fluorescence protein-Ras-binding domain (GFP-RBD), which efficiently bound to Ras in the GTP-bound state to competitively inhibit Ras activity (Fig. 1f and Supplementary Fig. S1f)
Summary
Ras proteins are essential components of the intracellular signaling cascades that regulate various fundamental cellular activities such as proliferation, apoptosis, differentiation, and senescence[1,2]. Ras interacts dynamically with specific microdomains of the plasma membrane and other internal cell membranes. These different membrane microenvironments modulate Ras signal output, highlighting the complex interplay between. Ras signaling in the plasma membrane is rapid and transient, whereas that in the Golgi apparatus is delayed and sustained[8]. Ras activates Raf-MEK-ERK in the plasma membrane and leads to cellular growth[6]. Cellular differentiation is induced when Ras activates Raf or PI3K in the Golgi apparatus[9,10]
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