Identification of a Key Motif That Determines the Differential Surface Levels of RET and TrkB Tyrosine Kinase Receptors and Controls Depolarization Enhanced RET Surface Insertion

Li, Xuezhi; Yan, Junkai; Huang, Shuhong; Zhao, Ling; Wang, Jue; Chen, Zhe-Yu

doi:10.1074/jbc.m111.283457

Cited by 6 publications

(4 citation statements)

References 40 publications

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“…, 2010 ). Another factor that has been shown to affect the ability of RET to traffic through the exocytic pathway is the phosphorylation status of threonine 675 in the juxtamembrane region of RET ( Li et al. , 2012 ).…”

Section: Discussionmentioning

confidence: 99%

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Alternative splicing results in RET isoforms with distinct trafficking properties

Richardson

Rodrigues

Hyndman

et al. 2012

MBoC

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Section: Discussionmentioning

confidence: 99%

“…, 2012 ). T675 can be phosphorylated by protein kinase C, and this phosphorylation was found to increase RET levels on the cell surface ( Li et al. , 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing results in RET isoforms with distinct trafficking properties

Richardson

Rodrigues

Hyndman

et al. 2012

MBoC

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“…We and others have shown that small size and slow cycling make AU1-LOV well suited for activation of membrane receptors by enabling dimer assembly for a sufficient duration [ 15 , 18 , 51 ]. We placed AU1-LOV at the far C-terminus of the RET receptors because fluorescent proteins were previously incorporated at this site without negative impact on receptor signaling or trafficking [ 52 , 53 ]. To functionally test the generated Opto-hRET and Opto-dRET, we took advantage of the fact that Drosophila RTKs can couple to the mammalian MAPK/ERK pathway via Ras [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

Optogenetic delivery of trophic signals in a genetic model of Parkinson’s disease

et al. 2021

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Optogenetics has been harnessed to shed new mechanistic light on current and future therapeutic strategies. This has been to date achieved by the regulation of ion flow and electrical signals in neuronal cells and neural circuits that are known to be affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and are implicated in degenerative disorders, has never been demonstrated in an animal model of disease. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson’s disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to inspire novel strategies towards a spatio-temporal regulation of tissue repair.

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“…We and others have shown that small size and slow cycling make AU1-LOV well suited for assembly and activation of membrane receptors (14,16,17,50). We placed AU1-LOV at the far C-terminus of the RET receptors because fluorescent proteins (FPs) were previously incorporated at this site without negative impact on receptor signaling or trafficking (51,52). To functionally test the generated Opto-hRET and Opto-dRET, we took advantage of the fact that Drosophila RTKs can couple to the mammalian MAPK/ERK pathway via Ras (44).…”

Section: Light-activated Hret and Dret Receptorsmentioning

confidence: 99%

Optogenetic delivery of trophic signals in a genetic model of Parkinson’s disease

Inglés-Prieto

Furthmann

Crossman

et al. 2020

Preprint

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Optogenetics has been harnessed to shed new mechanistic light on current therapies and to develop future treatment strategies. This has been to date achieved by the correction of electrical signals in neuronal cells and neural circuits that are affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and thereby may modify progression of degenerative disorders, has never been demonstrated in an animal disease model. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson’s disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to overcome limitations of current strategies towards a spatio-temporal regulation of tissue repair.Significance StatementThe death of physiologically important cell populations underlies of a wide range of degenerative disorders, including Parkinson’s disease (PD). Two major strategies to counter cell degeneration, soluble growth factor injection and growth factor gene therapy, can lead to the undesired activation of bystander cells and non-natural permanent signaling responses. Here, we employed optogenetics to deliver cell type-specific pro-survival signals in a genetic model of PD. In Drosophila and human cells exhibiting loss of the PINK1 kinase, akin to autosomal recessive PD, we efficiently suppressed disease phenotypes using a light-activated tyrosine kinase receptor. This work demonstrates a spatio-temporally precise strategy to interfere with degeneration and may open new avenues towards tissue repair in disease models.

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Identification of a Key Motif That Determines the Differential Surface Levels of RET and TrkB Tyrosine Kinase Receptors and Controls Depolarization Enhanced RET Surface Insertion

Cited by 6 publications

References 40 publications

Alternative splicing results in RET isoforms with distinct trafficking properties

Alternative splicing results in RET isoforms with distinct trafficking properties

Optogenetic delivery of trophic signals in a genetic model of Parkinson’s disease

Optogenetic delivery of trophic signals in a genetic model of Parkinson’s disease

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