GP78 Cooperates with Dual-Specificity Phosphatase 1 To Stimulate Epidermal Growth Factor Receptor-Mediated Extracellular Signal-Regulated Kinase Signaling.

GP78 is an autocrine motility factor (AMF) receptor (AMFR) with E3 ubiquitin ligase activity that plays a significant role in tumor cell proliferation, motility, and metastasis. Aberrant extracellular signal-regulated kinase (ERK) activation via receptor tyrosine kinases promotes tumor proliferation and invasion. The activation of GP78 leads to ERK activation, but its underlying mechanism is not fully understood.

The ubiquitin specific protease USP34 protects the ubiquitin ligase gp78 from proteasomal degradation.

The E3 ubiquitin (Ub) ligase gp78 plays an important role in endoplasmic reticulum (ER)-associated degradation (ERAD) and regulation of lipid biogenesis. Although a variety of substrates of gp78 have been described, the regulation of the degradation of gp78 itself remains poorly understood. To address this problem, we used co-immunoprecipitation-coupled liquid chromatography-tandem mass spectrometry (Co-IP/LC-MS/MS) to identify novel proteins interacting with gp78.

Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis.

Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis.

Elevated Coexpression of KITENIN and the ErbB4 CYT-2 Isoform Promotes the Transition from Colon Adenoma to Carcinoma Following APC loss.

Purpose And Experimental Design: The molecular events in the malignant progression of colon adenoma after loss of adenomatous polyposis coli (APC) are not fully understood. KITENIN (KAI1 C-terminal interacting tetraspanin) increases the invasiveness of colorectal cancer cells, and we identified a novel EGFR-independent oncogenic signal of EGF that works under coexpressed KITENIN and ErbB4. Here we tested whether elevated KITENIN and ErbB4 contribute to further progression of intestinal adenoma following APC loss.

Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2.

Induction of T-cell clonal anergy involves serial activation of transcription factors, including NFAT and Egr2/3. However, downstream effector mechanisms of these transcription factors are not fully understood yet. Here we identify Ndrg1 as an anergy factor induced by Egr2.

Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling.

Galectin-3 (Gal-3, LGALS3) is a pleotropic versatile, 29-35 kDa chimeric gene product, and involved in diverse physiological and pathological processes, including cell growth, homeostasis, apoptosis, pre-mRNA splicing, cell-cell and cell-matrix adhesion, cellular polarity, motility, adhesion, activation, differentiation, transformation, signaling, regulation of innate/adaptive immunity, and angiogenesis. In multiple diseases, it was found that the level of circulating Gal-3 is markedly elevated, suggesting that Gal-3-dependent function is mediated by specific interaction with yet an unknown ubiquitous cell-surface protein. Recently, we showed that Gal-3 attenuated drug-induced apoptosis, which is one of the mechanisms underlying multidrug resistance (MDR).

Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer.

Nonalcoholic steatohepatitis (NASH) is related to metabolic dysregulation and the perturbation of endoplasmic reticulum (ER) homeostasis that frequently develops into hepatocellular carcinoma (HCC). Gp78 is E3 ligase, which regulates endoplasmic reticulum-associated degradation (ERAD) by ubiquitinylation of misfolded ER proteins. Here, we report that upon ageing (12 months), gp78-/- mice developed obesity, recapitulating age-related human NASH.

The role of Cullin3-mediated ubiquitination of the catalytic subunit of PP2A in TRAIL signaling.

Protein phosphatase 2A (PP2A) is the major serine-threonine phosphatase that regulates a number of cell signaling pathways. PP2A activity is controlled partially through protein degradation; however, the underlying mechanism is not fully understood. Here we show that PP2A/C, a catalytic subunit of PP2A, is degraded by the Cullin3 (Cul3) ligase-mediated ubiquitin-proteasome pathway.

Galectin-3 inhibits osteoblast differentiation through notch signaling.

Patients with bone cancer metastasis suffer from unbearable pain and bone fractures due to bone remodeling. This is caused by tumor cells that disturb the bone microenvironment. Here, we have investigated the role of tumor-secreted sugar-binding protein, i.

Galectin-3 leads to attenuation of apoptosis through Bax heterodimerization in human thyroid carcinoma cells.

Cancer cells survive escaping normal apoptosis and the blocks in apoptosis that keep cancer cells alive are promising candidates for targeted therapy. Galectin-3 (Gal-3) is, a member of the lectin family, which is involved in cell growth, adhesion, proliferation and apoptosis. It remains elusive to understand the role of Gal-3 on apoptosis in thyroid carcinoma cells.

Polyubiquitylation of AMF requires cooperation between the gp78 and TRIM25 ubiquitin ligases.

gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25).

Autocrine motility factor modulates EGF-mediated invasion signaling.

Autocrine motility factor (AMF) enhances invasion by breast cancer cells, but how its secretion and effector signaling are controlled in the tumor microenvironment is not fully understood. In this study, we investigated these issues with a chimeric AMF that is secreted at high levels through a canonical endoplasmic reticulum (ER)/Golgi pathway. Using this tool, we found that AMF enhances tumor cell motility by activating AKT/ERK, altering actin organization, and stimulating β-catenin/TCF and activating protein 1 transcription.

Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells.

Trastuzumab (Herceptin) is an effective targeted therapy in HER2-overexpressing human breast carcinoma. However, many HER2-positive patients initially or eventually become resistant to this treatment, so elucidating mechanisms of trastuzumab resistance that emerge in breast carcinoma cells is clinically important. Here, we show that autocrine motility factor (AMF) binds to HER2 and induces cleavage to the ectodomain-deleted and constitutively active form p95HER2.

Tyrosine-phosphorylated galectin-3 protein is resistant to prostate-specific antigen (PSA) cleavage.

Galectin-3 is a chimeric carbohydrate-binding protein, which interacts with cell surface carbohydrate-containing molecules and extracellular matrix glycoproteins and has been implicated in various biological processes such as cell growth, angiogenesis, motility, and metastasis. It is expressed in a wide range of tumor cells and is associated with tumor progression. The functions of galectin-3 are dependent on its localization and post-translational modifications such as cleavage and phosphorylation.

Glycoprotein 90K, downregulated in advanced colorectal cancer tissues, interacts with CD9/CD82 and suppresses the Wnt/beta-catenin signal via ISGylation of beta-catenin.

Background And Aims: 90K, a tumour-associated glycoprotein, interacts with galectins and has roles in host defence by augmenting the immune response, but the serum 90K level was suggested to indicate poor prognosis in several cancers. The cellular mechanisms of 90K action on colorectal cancer (CRC) cell motility and its effect on CRC progression were investigated.

Methods: The impact of 90K was analysed by combining cell cultures, in vitro assays, and immunohistochemistry.

Brain-specific angiogenesis inhibitor 2 regulates VEGF through GABP that acts as a transcriptional repressor.

Previously, we reported that decreased brain-specific angiogenesis inhibitor 2 (BAI2) induced increased VEGF expression. The regulatory mechanisms for this process are not understood. Here we show that GA-binding protein gamma (GABPgamma) associates with the cytoplasmic domain of BAI2, and GABPalpha/gamma or GABPalpha/beta works as a transcriptional repressor of VEGF in SHSY5Y cells.

Suppression of progression and metastasis of established colon tumors in mice by intravenous delivery of short interfering RNA targeting KITENIN, a metastasis-enhancing protein.

KITENIN promotes invasion of mouse colon adenocarcinoma (CT-26) cells in vivo. Here, we studied the effects of in vivo KITENIN ablation on established tumors by using pSUPER vectors (pSUPER-KITENIN) producing short interfering RNA (siRNA). When pSUPER-KITENIN was given weekly or semiweekly for 1 month into tail vein of syngeneic mice that have established colon tumors, tumor size regressed markedly and metastases were inhibited.

Induction of manganese-containing superoxide dismutase is required for acid tolerance in Vibrio vulnificus.

The manganese-containing superoxide dismutase (MnSOD) of Vibrio vulnificus, normally detected after the onset of the stationary phase, is expressed during the lag that immediately follows the transfer of cells grown exponentially to a fresh medium acidified to pH 5.0, whereas Fe-containing SOD is constitutively expressed. The signal triggering the growth lag and MnSOD induction therein is not low pH but intracellular superoxide accumulated under these conditions, since addition of a superoxide scavenger not only shortened the lag but also abrogated the MnSOD induction.

Characterization of Cu- and Zn-containing superoxide dismutase of Rhodobacter sphaeroides.

Rhodobacter sphaeroides has a cuprozinc-containing superoxide dismutase (CuZnSOD) in its periplasm in addition to the cytoplasmic SOD that appears to contain iron (FeSOD). The FeSOD is constitutively expressed under the growth conditions examined, whereas the CuZnSOD is detected only when the light-harvesting complexes are found. The CuZnSOD expression is regulated post-transcriptionally, and the enzyme appears to protect the photoheterotrophic cells from periplasmic superoxide that may be generated by exposure of the cells to low O2 under the illuminated conditions at 10 W/m2.