Abstract
SummaryThe E3 ubiquitin ligase HUWE1, deregulated in carcinoma, has been implicated in tumor formation. Here, we uncover a role for HUWE1 in cell migration and invasion through degrading the RAC activator TIAM1, implying an additional function in malignant progression. In MDCKII cells in response to HGF, HUWE1 catalyzes TIAM1 ubiquitylation and degradation predominantly at cell-cell adhesions, facilitating junction disassembly, migration, and invasion. Depleting HUWE1 or mutating the TIAM1 ubiquitylation site prevents TIAM1 degradation, antagonizing scattering, and invasion. Moreover, simultaneous depletion of TIAM1 restores migration and invasion in HUWE1-depleted cells. Significantly, we show that HUWE1 stimulates human lung cancer cell invasion through regulating TIAM1 stability. Finally, we demonstrate that HUWE1 and TIAM1 protein levels are inversely correlated in human lung carcinomas. Thus, we elucidate a critical role for HUWE1 in regulating epithelial cell-cell adhesion and provide additional evidence that ubiquitylation contributes to spatiotemporal control of RAC.
Highlights
Metastasis, a multistep process beginning with local invasion and culminating in the colonization of distant organs by cancer cells, is responsible for more than 90% of all cancer deaths (Sleeman and Steeg, 2010)
Turnover was greatly increased in cells stimulated with hepatocyte growth factor (HGF) compared to control cells (Figures 1C and 1D)
Downregulation was via protein degradation as we observed no significant changes in the amount of mRNA following HGF treatment (Figure S1C), and the decrease in TIAM1 protein levels was significantly rescued by treating cells with MG132, a reversible proteasome inhibitor (Figures 1C and 1D)
Summary
Metastasis, a multistep process beginning with local invasion and culminating in the colonization of distant organs by cancer cells, is responsible for more than 90% of all cancer deaths (Sleeman and Steeg, 2010). Metastasis of carcinoma cells often commences with the disassembly of junctional complexes and downregulation of other epithelial traits coupled with the acquisition of a migratory and invasive mesenchymal phenotype (so-called epithelial-mesenchymal transition [EMT]). The HECT, UBA, and WWE domain-containing protein 1 (HUWE1) is a member of the HECT E3 ubiquitin ligase family whose substrates include key proteins such as p53 and MYC (Adhikary et al, 2005; Chen et al, 2005), which regulate diverse cellular responses including proliferation and survival with often opposing outcomes. HUWE1 has been ascribed both putative oncoprotein and tumor suppressor functions. Adding to this controversy, HUWE1 is overexpressed in some cancers but downregulated in others (Adhikary et al, 2005; Zhao et al, 2009). Further investigation is required to resolve the contribution of HUWE1 to tumorigenesis
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