Ubiquitination-mediated Regulation of Biosynthesis of the Adhesion Receptor SHPS-1 in Response to Endoplasmic Reticulum Stress

Abstract

Misfolding of proteins during endoplasmic reticulum (ER) stress results in the formation of cytotoxic aggregates. The ER-associated degradation pathway counteracts such aggregation through the elimination of misfolded proteins by the ubiquitin-proteasome system. We now show that SHP substrate-1 (SHPS-1), a transmembrane glycoprotein that regulates cytoskeletal reorganization and cell-cell communication, is a physiological substrate for the Skp1-Cullin1-NFB42-Rbx1 (SCF NFB42 ) E3 ubiquitin ligase, a proposed mediator of ER-associated degradation. SCF NFB42 mediated the polyubiquitination of immature SHPS-1 and its degradation by the proteasome. Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2␣ induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface. An NFB42 mutant lacking the F box domain had no such effects. Our results suggest that SCF NFB42 regulates SHPS-1 biosynthesis in response to ER stress.

Selective Cochlear Degeneration in Mice Lacking the F-Box Protein, Fbx2, a Glycoprotein-Specific Ubiquitin Ligase Subunit

“…Although results by others have supported the formation of full SCF complexes when Fbx2 is coexpressed with other subunits of SCF complexes in transfected cells (Yoshida et al, 2002;Murai-Takebe et al, 2004), we consistently failed to observe coprecipitation of Cullin1 and Rbx1 with endogenous Fbx2 in cochlear and brain extracts (Fig. 6a,b).…”

“…Levels of Cullin7 (another cullin expressed in the cochlea) are unchanged in KO mice. al., 2002;Murai-Takebe et al, 2004;Hagihara et al, 2005;Kato et al, 2005;Nelson et al, 2006). We propose that the loss of hearing observed in Fbxo2 Ϫ/Ϫ mice is caused by a failure of glycoprotein quality control in the organ of Corti.…”

Dna Microarray Analysis of Pulmonary Fibrosis Three Months After Exposure to Paraquat in Rats

“…As changes related to the pulmonary remodeling following exposure to PQ, the up-regulation of the expression of cofilin, which is involved in the depolymerization and cleavage of actin filaments, the LIM motif-containing protein kinase 1, which negatively regulates the activity of cofilin (Hotulainen et al, 2005;Prochniewicz et al, 2005;Willis et al, 2005), SHPS-1, which regulates the integrin-mediated reorganization of the cytoskeleton (Inagaki et al, 2000;Maile et al, 2003;Murai-Takebe et al, 2004) and sodium channel beta 2, which is involved in cell adhesion and migration (Kim et al, 2005) were observed.…”

FBG1 is a promiscuous ubiquitin ligase that sequesters APC2 and causes S-phase arrest

“…Fourth, this ubiquitin ligase degrades the adhesion receptor SHPS-1, which may be involved in tumor metastasis in melanomas and other cancers. [56][57][58] Finally, we show here that FBG1 interacts with APC2 and Cul7, both of which play important roles in lower levels. Second, in contrast to other FBG family members, FBG1 is not expressed during embryonic development and its expression increases in the brain during the first ten months of life.…”