Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

Degl’Innocenti, Debora; Arighi, Elena; Popsueva, Anna; Sangregorio, Romina; Alberti, Luisella; Rizzetti, Maria Grazia; Ferrario, Cristina; Sariola, Hannu; Borrello, Maria Grazia

doi:10.1038/sj.onc.1207862

Cited by 25 publications

(27 citation statements)

References 56 publications

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“…Each of these observations suggests an important role for Grb2 signaling in ENS development, a hypothesis supported by our Grb2 knockdown experiments with ENS precursor cells and by previous studies in vitro (35,37,38). Similar increases in the severity of observed defects were found in the parasympathetic and sympathetic ganglia, consistent with an important role for Grb2 in GFL-mediated nervous system development.…”

Section: Figuresupporting

confidence: 75%

“…Biochemical characterization of PI3K/AKT and MAPK activity in neurons from these mutant animals showed modest reductions in RET9(Y981F) and RET9(Y1015F) mutants and complete abrogation of PI3K/AKT and MAPK activity in RET9(Y1062F) mutants (29,39). These results are consistent with redundancy mediated by Grb2 interactions at Y1062 (via Shc) or direct binding at Y1096 and highlight the differences in RET51 versus RET9 signaling properties in vivo (35,37,38).…”

Section: Figuresupporting

confidence: 74%

“…Previous in vitro studies have presented contrasting views regarding the relative importance of these isoforms and each has been touted as more crucial (35,36). An additional study regarding the in vivo roles of Ret isoforms concluded that Ret51 could not support normal kidney or ENS development, whereas the formation of these systems was normal in Ret9-expressing mice (28).…”

Section: Figurementioning

confidence: 99%

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Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice

Jain¹,

Knoten²,

Hoshi³

et al. 2010

J. Clin. Invest.

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The receptor tyrosine kinase ret protooncogene (RET) is implicated in the pathogenesis of several diseases and in several developmental defects, particularly those in neural crest-derived structures and the genitourinary system. In order to further elucidate RET-mediated mechanisms that contribute to these diseases and decipher the basis for specificity in the pleiotropic effects of RET, we characterized development of the enteric and autonomic nervous systems in mice expressing RET9 or RET51 isoforms harboring mutations in tyrosine residues that act as docking sites for the adaptors Plcγ, Src, Shc, and Grb2. Using this approach, we found that development of the genitourinary system and the enteric and autonomic nervous systems is dependent on distinct RET-stimulated signaling pathways. Thus, mutation of RET51 at Y1062, a docking site for multiple adaptor proteins including Shc, caused distal colon aganglionosis reminiscent of Hirschsprung disease (HSCR). On the other hand, this mutation in RET9, which encodes an isoform that lacks the Grb2 docking site present in RET51, produced severe abnormalities in multiple organs. Mutations that abrogate RET-Plcγ binding, previously shown to produce features reminiscent of congenital anomalies of kidneys or urinary tract (CAKUT) syndrome, produced only minor abnormalities in the nervous system. Abrogating RET51-Src binding produced no major defects in these systems. These studies provide insight into the basis of organotypic specificity and redundancy in RET signaling within these unique systems and in diseases such as HSCR and CAKUT.

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Section: Figuresupporting

confidence: 75%

Section: Figuresupporting

confidence: 74%

Section: Figurementioning

confidence: 99%

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Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice

Jain¹,

Knoten²,

Hoshi³

et al. 2010

J. Clin. Invest.

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“…GDNF activates ERK, p38, PI3K, and Akt through binding to its receptor Ret (13,28,29), Therefore, reduced activity of ERK may be partly due to the decrease in GDNF. However, Ret is expressed only in the tips of ureteric buds.…”

Section: Articlesmentioning

confidence: 99%

Maternal nutrient restriction inhibits ureteric bud branching but does not affect the duration of nephrogenesis in rats

Awazu

Hida

2015

Pediatr Res

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Background: Maternal nutrient restriction produces offspring with fewer nephrons. We studied whether the reduced nephron number is due to the inhibition of ureteric branching or early cessation of nephrogenesis in rats. Signaling pathways involved in kidney development were also examined. Methods: The offspring of dams given food ad libitum (control (CON)) and those subjected to 50% food restriction (nutrient restriceted (NR)) were examined. results: At embryonic day 13 (E13), there was no difference between NR and CON in body weight or kidney size. Ureteric buds branched once in both NR and CON. At E14 and E15, body and kidney size were significantly reduced in NR. Ureteric bud tip numbers were also reduced to 50% of CON. On the other hand, the disappearance of nephrogenic zone and a nephron progenitor marker Cited1 was not different between CON and NR. The final glomerular number of NR was 80% of CON. Activated extracellular signal-regulated kinase (ERK), p38, PI3K, Akt, and mammallian target of rapamycin (mTOR), and protein expression of β-catenin were downregulated at E15. conclusion: Ureteric branching is inhibited and developmentally regulated signaling pathways are downregulated at an early stage by maternal nutrient restriction. These changes, not early cessation of nephrogenesis, may be a mechanism for the inhibited kidney growth and nephrogenesis. t he concept that disturbed intrauterine organogenesis affects the health and disease in the adulthood, termed developmental origins of health and disease, has been increasingly recognized. With respect to the kidney, low birth weight is associated with a risk for hypertension and renal disease, and reduced nephron number is considered to be the cause. In animals, maternal protein or global nutrient restriction, uterine artery ligation, hyperglycemia, and exposure to various agents such as glucocorticoids or alcohol produce offspring with fewer nephrons (1-6). Depletion of stem cells by increased apoptosis has been suggested to be responsible for the decreased nephron formation (1,3). On the other hand, ureteric bud branching is a fundamental step in determining nephron number. The mechanism of reduced nephron endowment in dexamethasone or ethanol exposure has been suggested to be inhibited branching morphogenesis in an organ culture study (5,7). Reduced ureteric branching has recently been reported in a model of maternal hyperglycemia in vivo (8).Another possible mechanism of reduced nephron number is early cessation of nephrogenesis. In human premature infants, nephrogenesis is reported to continue only up to 40 d after birth (9). These infants are under various stresses including hypoxia, infection, and medications adversely affecting nephrogenesis. It has been postulated that adverse conditions during development promote differentiation aiming at early maturation and survival at the expense of reduced organ growth. Newborn rats resemble human premature neonates in that nephrogenesis continues after birth. Early cessation of nephrogenesis, therefore, may b...

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“…As in all receptor tyrosine kinases, activation of Ret is associated with phosphorylation of specific tyrosine (Y) residues resulting in phosphotyrosine (pY) docking sites for intracellular adaptor and effector signaling molecules (39). Among such residues, pY1062 appears to have a critical role in signal initiation, serving as a docking site for protein complexes that activate both the MAPK and the PI3K signaling cascades (3,6,11,19,22,(26)(27)(28).…”

mentioning

confidence: 99%

Phosphotyrosine 1062 Is Critical for the In Vivo Activity of the Ret9 Receptor Tyrosine Kinase Isoform

Wong

Bogni²,

Kotka

et al. 2005

Molecular and Cellular Biology

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The receptor tyrosine kinase Ret plays a critical role in the development of the mammalian excretory and enteric nervous systems. Differential splicing of the primary Ret transcript results in the generation of two main isoforms, Ret9 and Ret51, whose C-terminal amino acid tails diverge after tyrosine (Y) 1062. Monoisoformic mice expressing only Ret9 develop normally and are healthy and fertile. In contrast, animals expressing only Ret51 have aganglionosis of the distal gut and hypoplastic kidneys. By generating monoisoformic mice in which Y1062 of Ret9 has been mutated to phenylalanine, we demonstrate that this amino acid has a critical role in Ret9 signaling that is necessary for the development of the kidneys and the enteric nervous system. These findings argue that the distinct activities of Ret9 and Ret51 result from the differential regulation of Y1062 by C-terminal flanking sequences. However, a mutation which places Y1062 of Ret51 in a Ret9 context improves only marginally the ability of Ret51 to support renal and enteric nervous system development. Finally, monoisoformic mice expressing a variant of Ret9 in which a C-terminal PDZ-binding motif was mutated develop normally and are healthy. Our studies identify Y1062 as a critical regulator of Ret9 signaling and suggest that Ret51-specific motifs are likely to inhibit the activity of this isoform.

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Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

Cited by 25 publications

References 56 publications

Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice

Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice

Maternal nutrient restriction inhibits ureteric bud branching but does not affect the duration of nephrogenesis in rats

Phosphotyrosine 1062 Is Critical for the In Vivo Activity of the Ret9 Receptor Tyrosine Kinase Isoform

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