A Golgi-based KDELR-dependent signalling pathway controls extracellular matrix degradation

Ruggiero, Carmen; Fragassi, Giorgia; Grossi, Mauro; Picciani, Benedetta; Martino, Rosaria Di; Capitani, Mirco; Buccione, Roberto; Luini, Alberto; Sallese, Michele

doi:10.18632/oncotarget.3270

Cited by 32 publications

(36 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…KDELR2, a transmembrane protein of the endoplasmic reticulum, can recognize proteins with KDEL (lam-aspartate-glut-leucine) tetrapeptide sequence, mediating these proteins' recycling from the Golgi back to the endoplasmic reticulum. It has been found that KDELR2 stimulates ECM degradation by inducing Src activation at the invadopodia and leads to phosphorylation of the Src substrates, cortactin, thereby promoting tumor metastasis and invasive growth (17). The expression level of KDELR2 in GBM was signi cantly higher than that of LGG and can be used as a prognostic marker for overall survival (6).…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of 4-gene prognostic signature in patients with diffuse gliomas based on gene expression profiles

Huang

Xiong

Li³

2020

Preprint

View full text Add to dashboard Cite

Background: Diffuse gliomas are a group of diseases that contain different degrees of malignancy and complex heterogeneity. Previous studies proposed biomarkers for certain grades of gliomas, but few of them have conducted a systematic analysis of different grades to search for molecular markers.Methods: WGCNA was used to find significant genes associated with malignant progression of diffuse glioma in TCGA glioma sequencing expression data and the GEO expression profile-merge meta dataset. Lasso regression was used for potential model building and the best model was selected by CPE, IDI and C_index. Risk score model was used to evaluate the gene signature prognostic power.Multi-omics data, including CNV, methylation, clinical traits and mutation, were used for model evaluation.Results: We find out 67 genes significantly associated with malignant progression of diffuse glioma by WGCNA. Next, we establish a new 4 gene molecular marker (KDELR2, EMP3, TIMP1, and TAGLN2).Multivariate cox analysis identified the risk score of the 4 genes as an independent predictor of prognosis in patients with diffuse gliomas, and its predictive power was independent of the histopathological grades of glioma. Further, we had confirmed in five independent test datasets and the risk score remained good predictive power. The combination of the prognosis model with specific molecular characteristics possessed better predictive power than risk score solely and we divided the low-risk group into three subtypes: LowRisk_IDH1wt, LowRisk_IDH1mut/ATRXmut, and LowRisk_IDH1mut/ATRXwt by combining IDH1 mutation with ATRX mutation, which possessed obvious survival difference. In further analysis, we found that the 4 gene prognosis model possessed multiomics features.Conclusion: we established a malignant-related 4-gene molecular marker by glioma expression profile data from multiple microarrays and sequencing data. The four markers had good predictive power on the overall survival of glioma patients and were associated with gliomas' clinical and genetic backgrounds, including clinical features, gene mutation, methylation, CNV, signal pathways.

show abstract

Section: Discussionmentioning

confidence: 99%

Systematic analysis of 4-gene prognostic signature in patients with diffuse gliomas based on gene expression profiles

Huang

Xiong

Li³

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…KDELR3 has neither been previously associated with cutaneous melanoma metastasis nor investigated in depth in the literature. Differences between KDELRs have been cited in the literature but the main focus has been the role of KDELR1 19,20,[43][44][45] . All three KDELR family members have been shown to mediate retrograde transport of proteins containing a Cterminus KDEL-like motif 19 .…”

Section: Discussionmentioning

confidence: 99%

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Marie

Sassano

Yang

et al. 2019

Preprint

View full text Add to dashboard Cite

Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posited that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover novel metastatic melanoma biology. We used a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, identified melanoblast-specific genes whose expression contributed to metastatic competence, and derived a 43-gene signature that predicted patient survival. We identified a melanoblast gene, KDELR3, whose loss impaired experimental metastasis. In contrast, KDELR1 deficiency enhanced metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover novel targetable pathways for melanoma therapy.Melanoma is an aggressive cancer that frequently progresses to metastatic proficiency. Treatment of metastatic melanoma remains a challenge, highlighting an urgent need to uncover new targets that could be used in the clinic to broaden therapeutic options. In the early 19 th century, Virchow first described cancer cells as being "embryonic-like" 1 . Developmental systems have since proven useful to study melanoma, and melanoma cell plasticity appears to be a key feature of melanoma progression. Melanocyte lineage pathways are a recurring theme in melanoma etiology, reinforcing the importance of uncovering new melanocyte developmental pathways and biology 2-13 . Here we use a genetically engineered mouse (GEM), designed to facilitate the isolation and analysis of developing melanocytes (melanoblasts), to attempt to uncover new targets relevant to melanoma metastasis.Melanocytes are neural crest-derived cells whose development necessitates extensive migration/invasion to populate the skin and other sites 14 . This process requires melanoblasts to adopt a migratory phenotype, to interact with and survive in foreign microenvironments and to colonize distant sites − functions that are analogous to metastatic competence 15 . To complete these processes, the cell may encounter numerous cellular stressors, such as shear stress, nutrient deprivation, hypoxia, lipid stress and oxidative stress 16 . The cellular impact of these stressors converges at the Endoplasmic Reticulum (ER), the organelle tied closely to protein synthesis and responsible for correct protein folding, protein quality control and post-translational modifications.Stress stimuli can result in aberrant ER function, a build-up of unfolded/misfolded proteins (ER stress), and an overwhelmed system. The ER can therefore be viewed as an exquisitely sensitive stress sensor. Upon ER stress insult, the ER launches an immediate counter measure known as of the Unfolded Protein Response (UPR) 17 . T...

show abstract

“…We have now found that KDELR knockdown by siRNA reduced egress of RSPs and DENV and have identified three positive charged amino acid residues at the N-terminus of prM that mediate interaction with KDELR in vitro [5]. Only KDELR1 and 2 were involved, similarly to what observed for ECM degradation [4]. However, an unexpected level of specificity was observed in that DENV4, one of the four serotypes, and West Nile virus, a member of the same Flaviviridae family, was not affected by KDELR depletion, suggesting that there might be some alternatives to KDELR-assisted transportation, an area that we are actively investigating.…”

mentioning

confidence: 93%

“…These findings place KDLER at the center of a complex system of signals, which originate at the Golgi but exert their effects at multiple levels. Two recent papers have shed new light on the role of KDELR by implicating them in as diverse functions as cell invasion [4] and virus infection [5]. …”

mentioning

confidence: 99%

“…Ruggiero et al zoomed in on the role of this molecular device in invadopodia formation, a Src-dependent process that requires activation of the exocytic machinery for extracellular matrix (ECM) degradation and invasive growth [4]. They found that persistent stimulation of KDELR increased ECM degradation, and that inhibition produced the expected opposite effect.…”

mentioning

confidence: 99%

See 1 more Smart Citation

New tricks for KDEL receptors

Li¹,

Bruzzone²,

Wang³

2015

Oncotarget

View full text Add to dashboard Cite

A Golgi-based KDELR-dependent signalling pathway controls extracellular matrix degradation

Cited by 32 publications

References 59 publications

Systematic analysis of 4-gene prognostic signature in patients with diffuse gliomas based on gene expression profiles

Systematic analysis of 4-gene prognostic signature in patients with diffuse gliomas based on gene expression profiles

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

New tricks for KDEL receptors

Contact Info

Product

Resources

About