Structure and Physiology of the RET Receptor Tyrosine Kinase

Ibáñez, Carlos F.

doi:10.1101/cshperspect.a009134

Cited by 137 publications

(114 citation statements)

References 87 publications

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“…The current view is that the activated GDNF-GFRα1-RET complex is a hexameric structure consisting of homodimers of GDNF, GFRα1 and RET [17]. Formation of this multimeric complex results in phosphorylation of specific tyrosine residues in the cytoplasmic domain (Figure 1b).…”

Section: Ret Signaling Componentsmentioning

confidence: 99%

To bud or not to bud: the RET perspective in CAKUT

2013

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Congenital anomalies of the kidneys or lower urinary tract (CAKUT) encompass a spectrum of anomalies that result from aberrations in spatio-temporal regulation of genetic, epigenetic, environmental and molecular signals at key stages of urinary tract development. The Rearranged in Transfection (RET) tyrosine kinase signaling system is a major pathway required for normal development of the kidneys, ureters, peripheral and enteric nervous systems. In the kidneys, RET is activated by interaction with the ligand glial cell line-derived neurotrophic factor (GDNF) and coreceptor GFRα1. This activated complex regulates a number of downstream signaling cascades (PLCγ, MAPK and PI3K) that control proliferation, migration, renewal and apoptosis. Disruption of these events is thought to underlie diseases arising from aberrant RET signaling. RET mutations are found in 5–30% of CAKUT patients and a number of Ret mouse mutants show a spectrum of kidney and lower urinary tract defects reminiscent of CAKUT in humans. The remarkable similarities between mouse and human kidney development and in defects due to RET mutations has led to using RET signaling as a paradigm to determine the fundamental principles in patterning of the upper and lower urinary tract and to understand CAKUT pathogenesis. In this review we provide an overview of studies in vivo that delineate expression and the functional importance of RET signaling complex during different stages of development of the upper and lower urinary tracts. We discuss how RET signaling balances activating and inhibitory signals emanating from its docking tyrosines and its interaction with upstream and downstream regulators to precisely modulate different aspects of Wolffian duct patterning and branching morphogenesis. We outline the diversity of cellular mechanisms regulated by RET, disruption of which causes malformations ranging from renal agenesis to multicystic dysplastic kidneys in the upper tract and vesicoureteral reflux or ureteropelvic junction obstruction in the lower tract.

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Section: Ret Signaling Componentsmentioning

confidence: 99%

To bud or not to bud: the RET perspective in CAKUT

2013

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“…We next set out to characterize Ret domains required for its function, focusing on the conserved N-terminal Cadherin-like domain (CLD), cysteine-rich domain (CRD), and its intracellular tyrosine kinase domain (Figure 4A; Ibáñez, 2013). We created Ret transgenes lacking extra- and intracellular domains or carrying a point mutation that impaired kinase activity (Ret K805M ; Abrescia et al, 2005) and assessed their ability to rescue C4da neuron dendrite development in Ret mutant animals.…”

Section: Resultsmentioning

confidence: 99%

“…Ret physically interacts with integrins to support C4da neuron dendrite-ECM adhesion via Rac1 signaling. In mammals, Ret signaling is believed to largely rely on binding of glial cell line-derived neurotrophic factor (GDNF) family ligands and the corresponding GDNF family co-receptors (Ibáñez, 2013). Although Ret is highly conserved in Drosophila (Hahn and Bishop, 2001; Hernández et al, 2015; Soba et al, 2015; Sugaya et al, 1994), GDNF homologs have not yet been identified in flies.…”

Section: Introductionmentioning

confidence: 99%

Ret and Substrate-Derived TGF-β Maverick Regulate Space-Filling Dendrite Growth in Drosophila Sensory Neurons

Hoyer

Zielke

et al. 2018

Cell Reports

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Summary Dendrite morphogenesis is a highly regulated process that gives rise to stereotyped receptive fields, which are required for proper neuronal connectivity and function. Specific classes of neurons, including Drosophila class IV dendritic arborization (C4da) neurons, also feature complete space-filling growth of dendrites. In this system, we have identified the substrate-derived TGF-β ligand maverick (mav) as a developmental signal promoting space-filling growth through the neuronal Ret receptor. Both are necessary for radial spreading of C4da neuron dendrites, and Ret is required for neuronal uptake of Mav. Moreover, local changes in Mav levels result in directed dendritic growth toward regions with higher ligand availability. Our results suggest that Mav acts as a substrate-derived secreted signal promoting dendrite growth within not-yet-covered areas of the receptive field to ensure space-filling dendritic growth.

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“…The RET (REarranged during Transfection) proto-oncogene is tightly associated with MTC development [3]. RET -activating germline point mutations are the driver events in MEN2 syndromes whereas somatic mutations of RET proto-oncogene are present in 30-50 % of sporadic MTC [1, 2].…”

Section: Introductionmentioning

confidence: 99%

“…RET -activating germline point mutations are the driver events in MEN2 syndromes whereas somatic mutations of RET proto-oncogene are present in 30-50 % of sporadic MTC [1, 2]. RET gene encodes a single-pass transmembrane tyrosine kinase receptor which is expressed in cells deriving from the branchial arches, the neural crest and the urogenital system [3, 4]. By direct phosphorylation of multiple downstream targets, the mutant RET tyrosine kinase receptor controls the proliferation and survival of MTC cells [3, 4].…”

Section: Introductionmentioning

confidence: 99%

Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer

et al. 2016

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Medullary thyroid cancer (MTC) relies on the aberrant activation of RET proto-oncogene. Though targeted approaches (i.e., tyrosine kinase inhibitors) are available, the absence of complete responses and the onset of resistance mechanisms indicate the need for novel therapeutic interventions. Due to their role in regulation of gene expression, G-quadruplexes (G4) represent attractive targets amenable to be recognized or stabilized by small molecules. Here, we report that exposure of MTC cells to a tri-substituted naphthalene diimide (NDI) resulted in a significant antiproliferative activity paralleled by inhibition of RET expression. Biophysical analysis and gene reporter assays showed that impairment of RET expression was consequent to the NDI-mediated stabilization of the G4 forming within the gene promoter. We also showed for the first time that systemic administration of the NDI in mice xenotransplanted with MTC cells resulted in a remarkable inhibition of tumor growth in vivo. Overall, our findings indicate that NDI-dependent RET G4 stabilization represents a suitable approach to control RET transcription and delineate the rationale for the development of G4 stabilizing-based treatments for MTC as well as for other tumors in which RET may have functional and therapeutic implications.

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Structure and Physiology of the RET Receptor Tyrosine Kinase

Cited by 137 publications

References 87 publications

To bud or not to bud: the RET perspective in CAKUT

To bud or not to bud: the RET perspective in CAKUT

Ret and Substrate-Derived TGF-β Maverick Regulate Space-Filling Dendrite Growth in Drosophila Sensory Neurons

Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer

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