Targeted mutation of serine 697 in the<i>Ret</i>tyrosine kinase causes migration defect of enteric neural crest cells

Asai, Naoya; Fukuda, Toshifumi; Wu, Zaiqi; Enomoto, Atsushi; Pachnis, Vassilis; Takahashi, Masahide; Costantini, Frank

doi:10.1242/dev.02616

Cited by 83 publications

(65 citation statements)

References 58 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activation of Ret by GDNF results in the activation of the MAP kinase pathways (van Weering & Bos 1997). Specifically, Ret activates the ERK and JNK signaling pathways (Marek et al 2004, Asai et al 2006. Our results showed that GDNF induced ERK, p38, JNK, and Akt phosphorylation in human colon cancer cells.…”

Section: Discussionmentioning

confidence: 55%

GDNF increases cell motility in human colon cancer through VEGF–VEGFR1 interaction

Huang

Chen

Chiu

et al. 2013

Endocrine-Related Cancer

View full text Add to dashboard Cite

Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor, has been shown to affect cancer cell metastasis and invasion. However, the molecular mechanisms underlying GDNF-induced colon cancer cell migration remain unclear. GDNF is found to be positively correlated with malignancy in human colon cancer patients. The migratory activities of two human colon cancer cell lines, HCT116 and SW480, were found to be enhanced in the presence of human GDNF. The expression of vascular endothelial growth factor (VEGF) was also increased in response to GDNF stimulation, along with VEGF mRNA expression and transcriptional activity. The enhancement of GDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Our results also showed that the expression of VEGF receptor 1 (VEGFR1) was increased in response to GDNF stimulation, whereas GDNF-induced cancer cell migration was reduced by a VEGFR inhibitor. The GDNF-induced VEGF expression was regulated by the p38 and PI3K/Akt signaling pathways. Treatment with GDNF increased nuclear hypoxia-inducible factor 1 a (HIF1a) accumulation and its transcriptional activity in a time-dependent manner. Moreover, GDNF increased hypoxia responsive element (HRE)-containing VEGF promoter transcriptional activity but not that of the HRE-deletion VEGF promoter construct. Inhibition of HIF1a by a pharmacological inhibitor or dominant-negative mutant reduced the GDNF-induced migratory activity in human colon cancer cells. These results indicate that GDNF enhances the migration of colon cancer cells by increasing VEGF-VEGFR interaction, which is mainly regulated by the p38, PI3K/Akt, and HIF1a signaling pathways.

show abstract

Section: Discussionmentioning

confidence: 55%

GDNF increases cell motility in human colon cancer through VEGF–VEGFR1 interaction

Huang

Chen

Chiu

et al. 2013

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…S3). These results demonstrate that early-onset syndromic deafness develops in c-Ret-KI Y1062F/Y1062F mice with severe HSCR (6) but not in c-Ret-KI S697A/S697A mice with mild HSCR (17).…”

Section: Resultsmentioning

confidence: 69%

“…These results suggest that c-Ret-KI Y1062F/Y1062F mice suffer from severe congenital deafness. On the other hand, hearing levels in other KI mice, in which serine 697 (S697, a putative protein kinase A phosphorylation site) in c-Ret was replaced with alanine (c-Ret-KI S697A/S697A mice), resulting in a mild HSCR phenotype (lack of the ENS limited to the distal colon) (17), were comparable to those in littermate WT mice (Fig. S3).…”

Section: Resultsmentioning

confidence: 83%

See 1 more Smart Citation

c-Ret–mediated hearing loss in mice with Hirschsprung disease

Ohgami

Ida-Eto

Shimotake

et al. 2010

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

Self Cite

View full text Add to dashboard Cite

A significantly increased risk for dominant sensorineural deafness in patients who have Hirschsprung disease (HSCR) caused by endothelin receptor type B and SOX10 has been reported. Despite the fact that c-RET is the most frequent causal gene of HSCR, it has not been determined whether impairments of c-Ret and c-RET cause congenital deafness in mice and humans. Here, we show that impaired phosphorylation of c-Ret at tyrosine 1062 causes HSCR-linked syndromic congenital deafness in c-Ret knockin (KI) mice. The deafness involves neurodegeneration of spiral ganglion neurons (SGNs) with not only impaired phosphorylation of Akt and NF-κB but decreased expression of calbindin D28k in inner ears. The congenital deafness involving neurodegeneration of SGNs in c-Ret KI mice was rescued by introducing constitutively activated RET. Taken together with our results for three patients with congenital deafness with c-RET-mediated severe HSCR, our results indicate that c-Ret and c-RET are a deafness-related molecule in mice and humans. spiral ganglion neuron | syndromic congenital deafness | tyrosine kinase A bout 30% of the 120 million people worldwide who suffer from congenital (early-onset) hearing loss are syndromic, and the remaining 70% are nonsyndromic (1-3). To elucidate the etiologies for the hearing losses, inner ears have been morphologically investigated as one of the target tissues. The inner ears contain the organ of Corti and the stria vascularis. The stria vascularis serves to maintain the endolymph potential. The organ of Corti, which consists of two kinds of sensory cells (inner hair cells and outer hair cells) is responsible for mechanotransduction, by which sound impulses are converted into neural impulses. Auditory information from the sensory cells is transmitted to spiral ganglion neurons (SGNs) as the primary carrier, followed by eventual transmission to the auditory cortex (1, 2

show abstract

“…Interestingly, this deficit could be alleviated by simultaneous mutation of the nearby residue Tyr 687 . On the basis of these findings, it has been suggested that phosphorylation of Ser 696 and Tyr 687 may induce opposite effects on RET signaling (16,17). However, the specific function of Tyr 687 has not been established.…”

mentioning

confidence: 99%

Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase

Perrinjaquet¹,

Vilar²,

Ibáñez

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The signaling mechanisms by which neurotrophic receptors regulate neuronal survival and axonal growth are still incompletely understood. In the receptor tyrosine kinase RET, a receptor for GDNF (glial cell line-derived neurotrophic factor), the functions of the majority of tyrosine residues that become phosphorylated are still unknown. Here we have identified the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr 687 in the juxtamembrane region of the receptor. We show that SHP2 is recruited to RET upon ligand binding in a cooperative fashion, such that both interaction with Tyr 687 and association with components of the Tyr 1062 signaling complex are required for stable recruitment of SHP2 to the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Furthermore, we find that activation of protein kinase A (PKA) by forskolin reduces the recruitment of SHP2 to RET and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of Ser 696 , a known PKA phosphorylation site in RET, enhances SHP2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. Together, these findings establish SHP2 as a novel positive regulator of the neurotrophic activities of RET and reveal Tyr 687 as a critical platform for integration of RET and PKA signals. We anticipate that several other phosphotyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions.Neurotrophic factors regulate neuronal survival, morphology, and function and are essential for the development and maintenance of the nervous system. Together with the neurotrophins, glial cell line-derived neurotrophic factor (GDNF) 4 and related family members are among the most important neurotrophic factors in mammals. Because of the potent prosurvival and neuroprotective effects of GDNF on midbrain dopaminergic neurons, much of the initial interest in GDNF was focused on its possible therapeutic effects in Parkinson disease (1, 2). It has more recently been appreciated that GDNF and related factors affect a host of important processes in mature neurons and their precursors and also outside the nervous system. GDNF signals by binding to a receptor complex formed by the ligand-binding subunit GFR␣1 and the signaling subunit RET, a member of the receptor tyrosine kinase (RTK) family (3). GFR␣1 also associates with the neural cell adhesion molecule, NCAM, to mediate the effects of GDNF independently of RET (4 -6). Some of the activities of GDNF can also be mediated by GFR␣1 in the absence of either RET or NCAM, suggesting alternative mechanisms of transmembrane signaling (7,8). A thorough understanding of the molecular mechanisms by which GDNF functions in different contexts will be essential to elucidating its contribution to nervous system development and exploiting its therapeutic poten...

show abstract

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

Cited by 83 publications

References 58 publications

GDNF increases cell motility in human colon cancer through VEGF–VEGFR1 interaction

GDNF increases cell motility in human colon cancer through VEGF–VEGFR1 interaction

c-Ret–mediated hearing loss in mice with Hirschsprung disease

Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase

Contact Info

Product

Resources

About