Abstract
Chaperone-assisted proteasome degradation of oncogenic protein acts as an upstream signal controlling tumorigenesis and progression. The understanding of the co-regulation of chaperone and oncoprotein of endocytosis pathways is extremely limited. In this study, we showed for the first time that proto-Dbl (dbl proto-oncogene product) is co-enriched with mitochondrial chaperone GRP75 in endocytosis vesicles from ovarian cancer cells. onco-Dbl, produced by oncogenic mutation/degradation of proto-Dbl, markedly enhanced cellular macropinocytosis but suppressed clathrin-mediated endocytosis and clathrin-independent endocytosis pathways, presenting a derailed endocytosis phenotype. GRP75 was associated with proto-Dbl inside cells and modulated Dbl-driven endocytosis derailed by a co-regulatory mode. In spite of not being a component of the Hsc70/Hsp90/proto-Dbl complex, the degradation of proto-Dbl was promoted by GRP75 through the CHIP-mediated ubiquitin–proteasome pathway, of which GRP75 acts as a cooperator with CHIP but also acts as a competitor to Hsc70 and Hsp90 in the multiple chaperones-assisted pro-folding/pro-degradation machinery. Knockdown or inhibition of GRP75 attenuated proto-Dbl degradation and reduced the onco-Dbl level, which differentially impaired Rho GTPases activation and therefore shifted the endocytosis-derailed phenotype. Our data uncovered a novel GRP75-Dbl endocytosis regulatory axis and provided an alternative using chaperone inhibitor to shut down the oncoprotein-driven endocytosis derailment mechanism.
Highlights
Abnormal membrane and vesicle trafficking constitute a derailed endocytosis phenotype, which has emerged as a multifaceted hallmark of cancer cells[1,2,3]
Co-enriched proto-Dbl with GRP75 in endocytosis vesicles We previously found that mitochondrial chaperone
GRP75 is present on cancer cell surfaces and enriched in heparan sulfate proteoglycan (HSPG)-induced endocytic vesicles with an uptake regulatory function[24,25,26]
Summary
Abnormal membrane and vesicle trafficking constitute a derailed endocytosis phenotype, which has emerged as a multifaceted hallmark of cancer cells[1,2,3]. The derailed endocytosis highly stimulates cancer cell uptake of certain nutrients to sustain their growth and proliferation in hostile microenvironments, and this characteristic develops an endocytosis-mediated defense system against therapeutic macromolecules[1,3,4,5]. Accumulation of oncoproteins activates downstream Rho GTPases, such as the three bestcharacterized Cdc[42], Rac[1], and RhoA, which induce distinct endocytosis changes[6]. Rho GTPases is facilitated by a family of oncoproteins known as Dbl Oncogenic activation of proto-Dbl, the dbl proto-oncogene product, occurs through loss of the amino-terminal residues, producing a constitutively active
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