Sortilin limits EGFR signaling by promoting its internalization in lung cancer

Al‐Akhrass, Hussein; Naves, Thomas; Vincent, François; Magnaudeix, Amandine; Durand, Karine; Bertin, F.; Melloni, B.; Jauberteau, Marie‐Odile; Lalloué, Fabrice

doi:10.1038/s41467-017-01172-5

Cited by 71 publications

(84 citation statements)

References 64 publications

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“…NTSR3 or sortilin 1 has been implicated in the loading of EGFR into exosomes and sortilin depletion maintains EGFR on the cell surface, limiting EGFR endocytosis [19]. NTSR3 normally cycles between the cell membrane and the trans-Gogi network.…”

Section: Lung Cancermentioning

confidence: 99%

“…NTSR3 binds both stimulated and unstimulated EGFR, leading to its internalization. This eventually leads to EGFR expulsion via exosomes or in receptor degradation and hence signal termination [19]. Al-Akhrass et al found that low sortilin expression was associated with increased cellular proliferation and tumour growth, indicating that NTSR3 is a favorable prognostic marker in lung adenocarcinoma patients [19].…”

Section: Lung Cancermentioning

confidence: 99%

“…This eventually leads to EGFR expulsion via exosomes or in receptor degradation and hence signal termination [19]. Al-Akhrass et al found that low sortilin expression was associated with increased cellular proliferation and tumour growth, indicating that NTSR3 is a favorable prognostic marker in lung adenocarcinoma patients [19]. His team also performed immunohistochemical analysis on 78 patients with NSCLCs (grades I-III; well to poorly differentiated); sortilin expression decreased significantly with pathologic grade and was associated with poorer prognosis [19].…”

Section: Lung Cancermentioning

confidence: 99%

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The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review

et al. 2020

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Background: Neurotensin, originally isolated in 1973 has both endocrine and neuromodulator activity and acts through its three main receptors. Their role in promoting tumour cell proliferation, migration, DNA synthesis has been studied in a wide range of cancers. Expression of Neurotensin and its receptors has also been correlated to prognosis and prediction to treatment. Main body: The effects of NT are mediated through mitogen-activated protein kinases, epidermal growth factor receptors and phosphatidylinositol-3 kinases amongst others. This review is a comprehensive summary of the molecular pathways by which Neurotensin and its receptors act in cancer cells. Conclusion: Identifying the role of Neurotensin in the underlying molecular mechanisms in various cancers can give way to developing new agnostic drugs and personalizing treatment according to the genomic structure of various cancers.

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Section: Lung Cancermentioning

confidence: 99%

Section: Lung Cancermentioning

confidence: 99%

Section: Lung Cancermentioning

confidence: 99%

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The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review

et al. 2020

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“…Ligand-binding to RTKs triggers receptor internalisation and trafficking within the cells which determines strength, duration and spatial distribution of EGFR signals [7][8][9][10][11] . RTKs, including EGFRs are internalised through clathrin-dependent and -independent mechanisms, converging on the delivery of the receptors to early endosomes 7 .…”

Section: Introductionmentioning

confidence: 99%

Ligand-independent role of ErbB3 in endocytic recycling

Saez-Ibañez

Scheffler

Terabayashi

et al. 2019

Preprint

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Running title: Integral role of ErbB3 in the endocytic recycling machineryIntegral role of ErbB3 in the endocytic recycling machinery 2 Abstract Internalisation and trafficking of activated receptor tyrosine kinases (RTKs) determines duration and spatial distribution of growth factor signalling. Here we show that the ErbB3 receptor, frequently overexpressed in invasive cancers, acts in a ligand-independent manner to sort cargo such as b1 integrins and the transferrin receptor (TfR) for endocytic recycling breast epithelial cells. Loss of ErbB3 abrogates recycling of b1 integrins from a Rab4-positive compartment and redirects it towards degradation.Consequently, delivery of b1 integrins to the leading front of migrating epithelial cells is impaired and cell migration compromised upon loss of ErbB3. Mechanistically, ErbB3 interacts with and stabilises the Rab4/5 effector rabaptin5 and the endosomal adaptor GGA3 thereby facilitating assembly of the Arf6-GGA3-rabaptin5 complex, required for recycling of cargo including integrins and TfR. We here show that ErbB3 is an integral part in the endosomal trafficking machinery, provoking the notion that RTKs might play a more instrumental role in vesicular trafficking than commonly perceived. IntroductionThe Epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (RTKs), including EGFR, ErbB2, ErbB3 and ErbB4, form homo-or heterodimers and play key roles in epithelial development and homeostasis while their deregulation contributes to most epithelial cancers 1 . Upon ligand-binding the RTK dimers are activated, leading to recruitment of signalling molecules that initiate intracellular signalling cascades. ErbB3 has limited kinase activity but growing evidence highlight its potent oncogenic activity. In particular, ErbB3 has been linked to the migratory behaviour and metastasis of cancer cells 2-5 . ErbB3 is also responsible for acquired resistance to anti-EGFR and -ErbB2 therapies, and thus an intensely pursued therapeutic target (reviewed 6 ).Ligand-binding to RTKs triggers receptor internalisation and trafficking within the cells which determines strength, duration and spatial distribution of EGFR signals 7-11 . RTKs, including EGFRs are internalised through clathrin-dependent and -independent mechanisms, converging on the delivery of the receptors to early endosomes 7 . Thereafter, the receptors are either diverted towards protein degradation via late endosomes/lysosomes or recycled back to the plasma membrane. Recycling of RTKs or other transmembrane proteins to the cell surface can occur either directly from early endosomes Integral role of ErbB3 in the endocytic recycling machinery 3 via a Rab4-dependent "short-loop" or via a Rab11-dependent "long-loop" endocytic recycling compartment 12 .Recently, the ubiquitously expressed GGA1 and GGA3 proteins, which are clathrin adaptors dependent on small GTPases of the Arf family, have been found to regulate Rab4-dependent endosomal recycling of b1 integrins (GGA3), transferrin receptor (GGA1) and Met RTK (GG...

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“…(3) Tyrosine-protein kinase Mer (MERTK) was reported to be overexpressed in human non-small cell lung cancer [61]. (4) Sortilin (SORT) was reported as a regulator of EGFR intracellular trafficking, which in turn impacts lung tumor growth [62]. It was also reported that the silencing sortilin expression in tumor cells may introduce sortilin as a potential candidate for developing a novel targeted therapy in patients with ovarian carcinoma [63].…”

Section: Parallel Reaction Monitoring (Prm) Validationmentioning

confidence: 99%

Early urinary protein changes in the tumor-forming process of the NuTu-19 lung metastasis

Wei

Meng

et al. 2019

Preprint

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The early detection of cancer is essential for effective intervention. Urine, which lacks homeostatic control, has been used to reflect early systemic changes in subcutaneous cancer models. However, urine has not been used to predict whether tumors will be formed in animal models. In this study, a cancer model was established by the tail-vein injection of 2 million NuTu-19 tumor cells. Approximately half of the rats formed lung metastatic carcinoma tumors. Urine samples were randomly selected from 4 tumor-forming rats and 4 non-tumor-forming rats on day 0/12/27/39/52 and analyzed by label-free proteomic quantitative analysis. Compared to day 0, a total of 180 and 118 urinary proteins in tumor-forming and non-tumor-forming rats, respectively, showed significant changes. Functional enrichment analysis of the differential proteins in tumor-forming rats revealed similar events during cancer metastasis cascades and tumor progression, such as the migration of tumor cell lines, coagulation system, TGF-β signaling, the STAT3 pathway and the adhesion of myeloid cells and alveolar macrophages. The differential proteins in non-tumor-forming rats were associated with agranulocyte/granulocyte adhesion and diapedesis, glutathione biosynthesis, IL-12 signaling and vitamin metabolism. After validation by parallel reaction monitoring (PRM) targeted proteomics quantitative analysis, a total of 22 urinary proteins showed significant changes in the early phase of the lung tumor formation process, 5 of which have been associated with the mechanisms of lung cancer, while 3 have been suggested as lung cancer biomarkers. Another 14 urinary proteins showed significant changes in the early phase in non-tumor-forming rats. Our results indicate that urine proteins could differentiate early tumor-forming and non-tumor-forming status.

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Sortilin limits EGFR signaling by promoting its internalization in lung cancer

Cited by 71 publications

References 64 publications

The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review

The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review

Ligand-independent role of ErbB3 in endocytic recycling

Early urinary protein changes in the tumor-forming process of the NuTu-19 lung metastasis

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