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

Wong, Adrianne L.; Bogni, Silvia; Kotka, Pille; Graaff, Esther de; D’Agati, Vivette D.; Costantini, Frank; Pachnis, Vassilis

doi:10.1128/mcb.25.21.9661-9673.2005

Cited by 82 publications

(69 citation statements)

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“…Although we did not observe any effect of the MEK1 inhibitor on ENCC migration in our gut culture system, this difference might be due to the different sensitivities of the different experimental systems, and/or to the different environmental conditions surrounding ENCCs in the whole-mount gut culture and in the chemoattractant assay. In accordance with the present result, we reported that mutant mice with the RET mutation Y1062F, which showed marked impairment of the PI3K/AKT signaling, developed aganglionosis in the whole ENS, supporting the view that the PI3K/AKT pathway is a critical signal for migration of ENCCs in the developing gut (Jain et al, 2004;Jijiwa et al, 2004;Wong et al, 2005). In addition, SRC kinase activity appears to play a role in the migration of ENCCs (Fig.…”

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confidence: 77%

Targeted mutation of serine 697 in theRettyrosine kinase causes migration defect of enteric neural crest cells

Asai

Fukuda

et al. 2006

Development

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The RET receptor tyrosine kinase plays a critical role in the development of the enteric nervous system (ENS) and the kidney. Upon glial-cell-line-derived neurotrophic factor (GDNF) stimulation, RET can activate a variety of intracellular signals, including the Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)/AKT, and RAC1/JUN NH 2 -terminal kinase (JNK) pathways. We recently demonstrated that the RAC1/JNK pathway is regulated by serine phosphorylation at the juxtamembrane region of RET in a cAMP-dependent manner. To determine the importance of cAMP-dependent modification of the RET signal in vivo, we generated mutant mice in which serine residue 697, a putative protein kinase A (PKA) phosphorylation site, was replaced with alanine (designated S697A mice). Homozygous S697A mutant mice lacked the ENS in the distal colon, resulting from a migration defect of enteric neural crest cells (ENCCs). In vitro organ culture showed an impaired chemoattractant response of the mutant ENCCs to GDNF. JNK activation by GDNF but not ERK, AKT and SRC activation was markedly reduced in neurons derived from the mutant mice. The JNK inhibitor SP600125 and the PKA inhibitor KT5720 suppressed migration of the ENCCs in cultured guts from wild-type mice to comparable degrees. Thus, these findings indicated that cAMP-dependent modification of RET function regulates the JNK signaling responsible for proper migration of the ENCCs in the developing gut.

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confidence: 77%

Targeted mutation of serine 697 in theRettyrosine kinase causes migration defect of enteric neural crest cells

Asai

Fukuda

et al. 2006

Development

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“…As a receptor tyrosine kinase, Ret can activate various signaling pathways, such as the RAS͞extracellular signal-regulated kinase, phosphatidylinositol 3-kinase͞AKT, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase pathways (41). These pathways are activated through phosphorylation of Tyr-1062 of Ret (42), a residue required for normal Ret function in vivo (43). Which of these pathways downstream of Ret are acting during the many phases of normal ENS development is unknown.…”

Section: Sox2 As a Potential Marker Of Proliferative And Stem Cell Pomentioning

confidence: 99%

Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes

Heanue

Pachnis

2006

Proc. Natl. Acad. Sci. U.S.A.

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The enteric nervous system (ENS) is composed of neurons and glial cells, organized as interconnected ganglia within the gut wall, which controls persistalsis of the gut wall and secretions from its glands. The Ret receptor tyrosine kinase is expressed throughout enteric neurogenesis and is required for normal ENS development; humans with mutations in the RET locus have Hirschsprung disease (HSCR, an absence of ganglia in the colon), and mice lacking Ret have total intestinal aganglionosis. The Ret mutant mouse provides a tool for identifying genes implicated in development of the ENS. By using RNA from WT and Ret mutant (aganglionic) gut tissue and DNA microarrays, we have conducted a differential screen for ENS-expressed genes and have identified hundreds of candidate ENS-expressed genes. Forty-seven genes were selected for further analysis, representing diverse functional classes. We show that all of the analyzed genes are expressed in the ENS and that the screen was sensitive enough to identify genes marking only subpopulations of ENS cells. Our screen, therefore, was reliable and sensitive and has identified many previously undescribed genes for studying ENS development. Moreover, two of the genes identified in our screen Arhgef3 and Ctnnal1, have human homologues that map to previously identified HSCR susceptibility loci, thus representing excellent candidates for HSCR genes. This comprehensive profile of ENS gene expression refines our understanding of ENS development and serves as a resource for future developmental, biochemical, and human genetic studies.T he enteric nervous system (ENS) is composed of a vast number of neurons and glial cells, which form interconnected ganglia that control the contractility of the smooth muscle of the gut wall and the secretory activity of its glands (1). The ENS is derived from vagal and sacral enteric neural crest cells (ENCs), which invade the foregut and hindgut, respectively (2, 3). Once situated within the gut, ENCs migrate along the developing bowel, proliferate, and differentiate to form many different neuronal subtypes and make synaptic connections (4, 5). Migration of ENCs within the gut requires signaling between these cells and the gut environment and depends on dynamic changes in cell shape and adhesive properties. How cell shape and adhesion are controlled to allow regulated and directed migration of ENCs currently is unknown. Furthermore, how cell fate decisions are controlled to specify the correct number and subtypes of neurons and glial cells within ENS ganglia or how correct synaptic circuits are established also is unknown.Genetic studies in mouse and human have identified several genes whose function is required for normal ENS development (6, 7). For example, the Ret receptor tyrosine kinase is expressed in ENCs during migration into the gut and persists during later ENS development (8). Humans carrying mutations in RET develop congenital megacolon [Hirschsprung disease (HSCR) OMIM 142623; ref. 7], which is characterized by the absence of enteric ga...

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“…RetY1015F mutants display spectrum of CAKUT-like defects, including supernumerary ureters, mega-ureters and dysplasia, as well as abnormally positioned gonads and failure of gonadal ducts to separate from the ureter. RetY1062F mutants show rudimentary kidneys, hypoplasia or agenesis (Jain et al, 2006a;Jain et al, 2004;Jijiwa et al, 2004;Wong et al, 2005). The molecular, cellular and developmental basis for disparate defects encompassing a wide range of CAKUT in these mutants is not known.…”

Section: Introductionmentioning

confidence: 99%

Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice

et al. 2012

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SUMMARYMutations in the receptor tyrosine kinase RET are associated with congenital anomalies of kidneys or urinary tract (CAKUT). RET tyrosine Y1015 is the docking site for PLC, a major regulator of RET signaling. Abrogating signaling via Y1015 causes CAKUT that are markedly different than renal agenesis in Ret-null or RetY1062F mutant mice. We performed analysis of Y1015F mutant upper and lower urinary tracts in mice to delineate its molecular and developmental roles during early urinary tract formation. We found that the degeneration of the common nephric ducts (CND), the caudal-most Wolffian duct (WD) segment, depends on Y1015 signals. The CNDs in Y1015F mutants persist owing to increased proliferation and reduced apoptosis, and showed abundance of phospho-ERK-positive cells. In the upper urinary tract, the Y1015 signals are required for proper patterning of the mesonephros and metanephros. Timely regression of mesonephric mesenchyme and proper demarcation of mesonephric and metanephric mesenchyme from the WD depends on RetY1015 signaling. We show that the mechanism of de novo ectopic budding is via increased ERK activity due to abnormal mesenchymal GDNF expression. Although reduction in GDNF dosage improved CAKUT it did not affect delayed mesenchyme regression. Experiments using whole-mount immunofluorescence confocal microscopy and explants cultures of early embryos with ERK-specific inhibitors suggest an imbalance between increased proliferation, decreased apoptosis and increased ERK activity as a mechanism for WD defects in RetY1015F mice. Our work demonstrates novel inhibitory roles of RetY1015 and provides a possible mechanistic explanation for some of the confounding broad range phenotypes in individuals with CAKUT.

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

Cited by 82 publications

References 50 publications

Targeted mutation of serine 697 in theRettyrosine kinase causes migration defect of enteric neural crest cells

Targeted mutation of serine 697 in theRettyrosine kinase causes migration defect of enteric neural crest cells

Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes

Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice

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