Regulation of EGFR signal transduction by analogue-to-digital conversion in endosomes

Villaseñor, Roberto; Nonaka, Hiroshi; Conte-Zerial, Perla Del; Kalaidzidis, Yannis; Zerial, Marino

doi:10.7554/elife.06156

Cited by 102 publications

(108 citation statements)

References 80 publications

(117 reference statements)

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“…This work confirms and extends the prior work done in liver parenchyma (32). Phosphotyrosine dephosphorylation of activated RTK is responsible for the termination of signal transduction.…”

Section: -Chx + Chxsupporting

confidence: 90%

“…Endosome-recruited phosphotyrosine phosphatases dephosphorylate the activated EGF-RTK. The protein tyrosine phosphatase, nonreceptor/Src homology 2 (SH2) (PTPN11/SHP2) domain has been identified as the relevant phosphotyrosine phosphatase based on RNAi screens affecting endosomal signaling (32). This same phosphotyrosine phosphatase also regulates EGF signaling in Drosophila melanogaster embryos.…”

Section: Endosome Fusion and The Regulation Of Signalingmentioning

confidence: 99%

“…In this way, early endosome membrane fusion is regulated. This regulation generates signaling endosomes in which RTK autophosphorylation and RTK tyrosine phosphorylation of SHC occur (32). An attenuation mechanism thus balances signaling with RTK inactivation.…”

Section: Endosome Fusion and The Regulation Of Signalingmentioning

confidence: 99%

“…FRET signal for colocalization was detected with 458-nm excitation and 593-nm longpass spectral range using high-resolution confocal microscopy. for the EGF-RTK in HeLa cells, the nerve growth factor (NGF) receptor in PC12 cells, and the hepatocyte growth factor receptor MET (mesenchymal-epithelial transition factor) in hepatoblasts (32).…”

Section: Figurementioning

confidence: 99%

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Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

Bergeron

Guglielmo

Dahan

et al. 2016

Annu. Rev. Biochem.

104

100

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Epidermal growth factor (EGF) and insulin receptor tyrosine kinases (RTKs) exemplify how receptor location is coupled to signal transduction. Extracellular binding of ligands to these RTKs triggers their concentration into vesicles that bud off from the cell surface to generate intracellular signaling endosomes. On the exposed cytosolic surface of these endosomes, RTK autophosphorylation selects the downstream signaling proteins and lipids to effect growth factor and polypeptide hormone action. This selection is followed by the recruitment of protein tyrosine phosphatases that inactivate the RTKs and deliver them by membrane fusion and fission to late endosomes. Coincidentally, proteinases inside the endosome cleave the EGF and insulin ligands. Subsequent inward budding of the endosomal membrane generates multivesicular endosomes. Fusion with lysosomes then results in RTK degradation and downregulation. Through the spatial positioning of RTKs in target cells for EGF and insulin action, the temporal extent of signaling, attenuation, and downregulation is regulated.

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“…This work confirms and extends the prior work done in liver parenchyma (32). Phosphotyrosine dephosphorylation of activated RTK is responsible for the termination of signal transduction.…”

Section: -Chx + Chxsupporting

confidence: 90%

Section: Endosome Fusion and The Regulation Of Signalingmentioning

confidence: 99%

Section: Endosome Fusion and The Regulation Of Signalingmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

Bergeron

Guglielmo

Dahan

et al. 2016

Annu. Rev. Biochem.

104

100

View full text Add to dashboard Cite

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“…Besides assembling on the plasma membrane, EGF-EGFR complexes also nucleate on endosomes, which are suggested to induce and fine-tune the amplitude and frequency of EGFR signaling [16,49,50]. Therefore, integrity and proper trafficking of endosomes are essential for EGF-EGFR signaling.…”

Section: Discussionmentioning

confidence: 99%

Loss of Maspardin Attenuates the Growth and Maturation of Mouse Cortical Neurons

Davenport

Bivona²,

Latson³

et al. 2016

Neurodegener Dis

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Background: Mast syndrome, an autosomal recessive, progressive form of hereditary spastic paraplegia, is associated with mutations in SPG21 loci that encode maspardin protein. Although SPG21^-/- mice exhibit lower limb dysfunction, the role of maspardin loss in mast syndrome is unclear. Objective: To test the hypothesis that loss of maspardin attenuates the growth and maturation of cortical neurons in SPG21^-/- mice. Methods and Results: In a randomized experimental design SPG21^-/- mice demonstrated significantly less agility and coordination compared to wild-type mice in beam walk, ledge, and hind limb clasp tests for assessing neuronal dysfunction (p ≤ 0.05). The SPG21^-/- mice exhibited symptoms of mast syndrome at 6 months which worsened in 12-month-old cohort, suggesting progressive dysfunction of motor neurons. Ex vivo, wild-type cortical neurons formed synapses, ganglia and aggregates at 96 h, whereas SPG21^-/- neurons exhibited attenuated growth with markedly less axonal branches. Additionally, epidermal growth factor markedly promoted the growth and maturation of SPG21^+/+ cortical neurons but not SPG21^-/- neurons. Consequently, quantitative RT-PCR identified a significant reduction in the expression of a subset of EGF-EGFR signaling targets. Conclusions: Our current study uncovered a direct role for maspardin in normal and EGF-induced growth and maturation of primary cortical neurons. The loss of maspardin resulted in attenuated growth, axonal branching, and attenuation of EGF signaling. Reinstating the functions of maspardin may reverse hind limb impairment associated with neuronal dysfunction in mast syndrome patients.

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Emerging functions of the EGFR in cancer

2017

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The physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as ‘noncanonical’) functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand‐induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress‐induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications.

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Regulation of EGFR signal transduction by analogue-to-digital conversion in endosomes

Cited by 102 publications

References 80 publications

Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction

Loss of Maspardin Attenuates the Growth and Maturation of Mouse Cortical Neurons

Emerging functions of the EGFR in cancer

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