GGA3-mediated recycling of the RET receptor tyrosine kinase contributes to cell migration and invasion

Crupi, Mathieu J. F.; Maritan, Sarah M.; Reyes-Alvarez, Eduardo; Lian, Eric; Hyndman, Brandy D.; Rekab, Aisha N.; Moodley, Serisha; Antonescu, Costin N.; Mulligan, Lois M.

doi:10.1038/s41388-019-1068-z

Cited by 23 publications

(34 citation statements)

References 46 publications

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“…We show that ErbB3 interacts with both GGA3 (via its VHS domain) and Rabaptin5 to promote assembly and stability of the Arf6-GGA3-Rabaptin5 endosomal sorting complex. GGA3 has previously been reported to be required to sort multiple cargos, such as β1 integrins, c-Met and c-Ret for Rab4-dependent recycling 16,17,20 Rabaptin5. This is in line with previous work showing that GGA3 is enriched in Rab4-positive endosomes along with endocytosed Met, and to a much lesser extent Rab5-positive early endosomes.…”

Section: Discussionmentioning

confidence: 99%

“…Among them, the Rab4-dependent "short-loop" and the Rab11-dependent "long-loop" recycling constitute two major pathways followed by RTKs and other transmembrane proteins, including integrins 12,13 . Recently, the ubiquitously expressed GGA1-3 proteins, which are clathrin adaptors dependent on small GTPases of the Arf family, have been found to regulate Rab4 or -11-dependent endosomal recycling of β1 integrins (GGA2, GGA3), Transferrin receptor (TfR) (GGA1), Met RTK and Ret RTK (GGA3) [14][15][16][17][18][19][20] . GGA proteins contain several functional domains that, for example, bind accessory proteins that modulate membrane trafficking such as Rabaptin5 18,21,22 .…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ligand-independent role of ErbB3 in endocytic recycling

Saez-Ibañez

Scheffler

Terabayashi

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…P =< 0.05*, < 0.01**, < 0.001*** (one-way ANOVA with Tukey test). We have previously shown that FGF10-mediated FGFR2b recycling regulates cell migration (Francavilla et al, 2013) and RTK recycling is known to increase cell motility (Crupi et al, 2020). As FGFR2b recycling was impaired in T693A-expressing cells (Fig 5), we then investigated whether EGFR_T693 phosphorylation was required for cell invasion.…”

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confidence: 95%

Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs

Smith

Ferguson

et al. 2021

The EMBO Journal

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Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine-tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling-dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGFmediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers.

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“…Finally, FGF10-dependent EGFR_T693 phosphorylation plays a crucial role in FGF10 priming of EGFR responses, as shown by decreased EdU incorporation in T693A-expressing T47D and BT20 cells stimulated with FGF10 for 40 min prior to TGFa treatment ( Figure 7C-D). We have previously shown that FGF10-mediated FGFR2b recycling regulates cell migration (Francavilla et al, 2013) and RTK recycling is known to increase cell motility (Crupi et al, 2020). As FGFR2b recycling was impaired in T693A-expressing cells ( Figure 5), we then investigated whether EGFR_T693 phosphorylation was required for cell invasion.…”

Section: Outputsmentioning

confidence: 96%

Reciprocal Priming between Receptor Tyrosine Kinases at Recycling Endosomes Orchestrates Cellular Signalling Outputs

Smith

Ferguson

et al. 2021

Preprint

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SUMMARYIntegration of signaling downstream from individual Receptor Tyrosine Kinases (RTKs) is crucial to fine tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration still remain poorly elucidated. Focusing on distinct Fibroblast Growth Factor Receptors (FGFRs) we generated a detailed picture of recycling-dependent FGF signalling in breast cancer cells by combining quantitative phosphoproteomics and targeted assays. We discovered reciprocal priming between FGFRs and Epidermal Growth Factor Receptor (EGFR) within recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated cell cycle but not cell invasion. In turn, FGFR signaling primes EGF-mediated outputs. The discovery of reciprocal priming between distict families of RTKs within recycling endosomes will transform our understanding of signalling integration by pointing to recycling endosomes as crucial signalling hubs for orchestrating cellular behaviour. Therefore, targeting reciprocal priming rather than individual receptors may improve personalized therapies in breast and other cancers.

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GGA3-mediated recycling of the RET receptor tyrosine kinase contributes to cell migration and invasion

Cited by 23 publications

References 46 publications

Ligand-independent role of ErbB3 in endocytic recycling

Ligand-independent role of ErbB3 in endocytic recycling

Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs

Reciprocal Priming between Receptor Tyrosine Kinases at Recycling Endosomes Orchestrates Cellular Signalling Outputs

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