SORLA regulates endosomal trafficking and oncogenic fitness of HER2

Pietilä, Mika; Sahgal, Pranshu; Peuhu, Emilia; Jäntti, Niklas Z.; Paatero, Ilkka; Närvä, Elisa; Al‐Akhrass, Hussein; Lilja, Johanna; Γεωργιάδου, Μαρία; Andersen, Olav M.; Padzik, Artur; Sihto, Harri; Joensuu, Heikki; Blomqvist, Matias; Saarinen, Irena; Boström, Peter J.; Taimen, Pekka; Ivaska, Johanna

doi:10.1038/s41467-019-10275-0

Cited by 55 publications

(85 citation statements)

References 51 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Internalized virus particles in early endosomes are delivered to late endosomes/lysosomes in which membrane fusion occurs. Co-localization of the HER2/ TYRO3 complex and the EBOVΔVP30 particles was detected only when the virus particles were on the cell surface and was no longer detected after internalization (Fig 7E), which may be because HER2 is quickly recycled to the cell surface or is resistant to internalization [40,41]. A similar observation was reported for AXL co-localization with a pseudotyped virus with EBOV GP on its cell surface; their co-localization was not detected once the virus entered the cells [21].…”

Section: Discussionmentioning

confidence: 99%

HER2-mediated enhancement of Ebola virus entry

2020

View full text Add to dashboard Cite

Multiple cell surface molecules including TAM receptors (TYRO3, AXL, and MERTK), a family of tyrosine kinase receptors, can serve as attachment receptors for Ebola virus (EBOV) entry into cells. The interaction of these receptors with EBOV particles is believed to trigger the initial internalization events that lead to macropinocytosis. However, the details of how these interactions lead to EBOV internalization have yet to be elucidated. Here, we screened receptor tyrosine kinase (RTK) inhibitors for anti-EBOV activity by using our previously established biologically contained Ebola virus that lacks the VP30 gene (EBOVΔVP30) and identified several RTKs, including human epidermal growth factor receptor 2 (HER2), as potential targets of anti-EBOV inhibitors and as novel host factors that have a role in EBOV infection. Of these identified RTKs, it was only HER2 whose knockdown by siRNAs impaired EBOVΔVP30-induced AKT1 phosphorylation, an event that is required for AKT1 activation and subsequent macropinocytosis. Stable expression of HER2 resulted in constitutive activation of AKT1, resulting in the enhancement of EBOVΔVP30 growth, EBOV GP-mediated entry, and macropinocytosis. Moreover, we found that HER2 interacts with the TAM receptors, and in particular forms a complex with TYRO3 and EBOVΔVP30 particles on the cell surface. Interestingly, HER2 was required for EBOVΔVP30-induced TYRO3 and AKT1 activation, but the other TAM receptors (TYRO3 and MERTK) were not essential for EBOVΔVP30-induced HER2 and AKT1 activation. Our findings demonstrate that HER2 plays an important role in EBOV entry and provide novel insights for the development of therapeutics against the virus.

show abstract

Section: Discussionmentioning

confidence: 99%

HER2-mediated enhancement of Ebola virus entry

2020

View full text Add to dashboard Cite

show abstract

“…Similar studies have been conducted in other types of tumors. Mika et al found the SORLA-dependent molecular pathway in HER2-driven cancers [46]. Yoshihisa et al suggested that syn-miR-143 down-regulated the expression of HER2 through silencing DEAD/H-box RNA helicase 6 (DDX6) in HER2-positive gastric cancer cells [47].…”

Section: Discussionmentioning

confidence: 99%

The Clinical Significance and Prognostic Value of HER2 Expression in Bladder Cancer: a Systematic Review and Meta-analysis

Gan¹,

Gao²,

Liu³

et al. 2020

Preprint

View full text Add to dashboard Cite

Objective: Human Epidermal Growth Factor Receptor 2 (HER2) is highly expressed in a variety of tumors and associated with patients’ prognosis, but its role in bladder cancer remains unclear. We conducted this meta-analysis to explore the clinical significance and prognostic value of HER2 in bladder cancer and its potentiality as an immunotherapy target.Methods: PubMed was searched for studies published between January 1, 2000 and January 1, 2020. The odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95%CIs) were used to investigate the relationship between HER2 and bladder cancer. UALCAN website was used to obtain TCGA (The cancer genome atlas) database.Results: Our study includes 14 articles, 1398 patients. HER2 expression was significantly higher in bladder cancer than in normal tissues. Our meta-analysis results did not reveal any effect of gender on the expression of HER2 levels in bladder cancer patients. However, HER2 expression in male patients was significantly higher than that in women according to TCGA databases. HER2 expression was also associated with carcinoma in situ, multifocal tumors, large tumor size, high tumor stage and grade, lymph node metastases, risk of recurrence and progression, low recurrence-free survival (RFS) rate. HER2 expression status had no effect on overall survival.Conclusions: Our meta-analysis showed that HER2 expression was related to pathological malignancy and poor prognosis in bladder cancer which indicated that it could be used as an effective biomarker and therapeutic target.

show abstract

“…These studies underline the versatility of LRP1 functions in breast TME and support ongoing research to identify the specific molecular interfaces mobilized by the receptor that could be targeted to control aggressive behavior of tumor cells. A less characterized member of LRPs, SorLA/LRP11, was recently involved in the endocytic trafficking of HER2 ( 20 ). The depletion of SorLA was reported to affect lysosomal function and sensitize HER2-overexpressing cells resistant to targeted therapy.…”

Section: Lrps and Breast Cancer Cells: A Close And Complex Relationshmentioning

confidence: 99%

Contribution of the Low-Density Lipoprotein Receptor Family to Breast Cancer Progression

et al. 2020

View full text Add to dashboard Cite

The low-density lipoprotein receptor (LDLR) family comprises 14 single-transmembrane receptors sharing structural homology and common repeats. These receptors specifically recognize and internalize various extracellular ligands either alone or complexed with membrane-spanning co-receptors that are then sorted for lysosomal degradation or cell-surface recovery. As multifunctional endocytic receptors, some LDLR members from the core family were first considered as potential tumor suppressors due to their clearance activity against extracellular matrix-degrading enzymes. LDLRs are also involved in pleiotropic functions including growth factor signaling, matricellular proteins, and cell matrix adhesion turnover and chemoattraction, thereby affecting both tumor cells and their surrounding microenvironment. Therefore, their roles could appear controversial and dependent on the malignancy state. In this review, recent advances highlighting the contribution of LDLR members to breast cancer progression are discussed with focus on (1) specific expression patterns of these receptors in primary cancers or distant metastasis and (2) emerging mechanisms and signaling pathways. In addition, potential diagnosis and therapeutic options are proposed.

show abstract

SORLA regulates endosomal trafficking and oncogenic fitness of HER2

Cited by 55 publications

References 51 publications

HER2-mediated enhancement of Ebola virus entry

HER2-mediated enhancement of Ebola virus entry

The Clinical Significance and Prognostic Value of HER2 Expression in Bladder Cancer: a Systematic Review and Meta-analysis

Contribution of the Low-Density Lipoprotein Receptor Family to Breast Cancer Progression

Contact Info

Product

Resources

About