Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor

  title={Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor},
  author={Hironori Hayashi and Masatoshi Ichihara and Toshihide Iwashita and Hideki Murakami and Yohei Shimono and Kumi Kawai and Kei Kurokawa and Yoshiki Murakumo and Tsuneo Imai and Hiroomi Funahashi and Akimasa Nakao and Masahide Takahashi},
Glial cell line derived neurotrophic factor (GDNF) signals through a multicomponent receptor complex consisting of RET receptor tyrosine kinase and a member of GDNF family receptor α (GFRα). Recently, it was shown that tyrosine 1062 in RET represents a binding site for SHC adaptor proteins and is crucial for both RAS/mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from… 

Gas1 reduces Ret tyrosine 1062 phosphorylation and alters GDNF-mediated intracellular signaling

Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation.

Investigation of whether glial cell line-derived neurotrophic factor (GDNF) can induce activation of BMK1 through RET tyrosine kinase revealed that RET-MEN2A mutant proteins can activate the MEF2C transcription factor, and that its activation is impaired by the Y1062F mutation or by expression of a dominant negative form of MEK5.

The Neuron-Specific Rai (ShcC) Adaptor Protein Inhibits Apoptosis by Coupling Ret to the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway

It is proposed that Rai potentiates the MAPK and PI3K signaling pathways and regulates Ret-dependent and -independent survival signals.

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

This work identifies the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr687 in the juxtamembrane region of the receptor and reveals Tyr687 as a critical platform for integration ofRET and PKA signals.

Control of neuronal survival, migration and outgrowth by GDNF and its receptors

This thesis demonstrated new insights into the control of neuronal survival, migration, and outgrowth by GDNF and its receptors and justified the existence of a novel transmembrane receptor for the GDNF/GFR!1 complex and uncovered an unexpected interplay between GD NF/G FR!1 and HGF/Met signaling in the early diversification of GABAergic MGE interneuron subtypes.

Glial Cell Line-derived Neurotrophic Factor-stimulated Phosphatidylinositol 3-Kinase and Akt Activities Exert Opposing Effects on the ERK Pathway

Findings underscore the importance of the Ret/PI3K/Akt pathway in GDNF-induced neuroectodermic cell survival and find that Akt activation is indispensable for counteracting the apoptotic signal on mitochondria, whereas ERK is partially involved in precluding procaspase-3 cleavage.

Dok-4 regulates GDNF-dependent neurite outgrowth through downstream activation of Rap1 and mitogen-activated protein kinase

Dok-4, through activation of the Rap1-ERK1/2 pathway, regulates GDNF-mediated neurite outgrowth during neuronal development, and neurite formation in cultured rat hippocampal neurons was enhanced by the expression of Dok- 4.



Ret-dependent and -independent Mechanisms of Glial Cell Line-derived Neurotrophic Factor Signaling in Neuronal Cells*

Compared signaling pathways activated by GDNF in two neuronal cell lines expressing different complements of GDNF receptors are compared to indicate the existence of novel signaling mechanisms directly or indirectly mediated by GFRα receptors acting in a cell-autonomous manner independently of Ret.

Calcium-dependent Ret activation by GDNF and neurturin

The results demonstrated that Ca2+ ions might be required for the complex formation of Ret and GDNF or NTN that induces Ret oligomerization and autophosphorylation, which suggested that full morphological differentiation of neuroblastoma cells by these neurotrophic factors was also Ca2-dependent.

Glial Cell Line-derived Neurotrophic Factor Induces Ret-mediated Lamellipodia Formation*

It is shown that glial cell line-derived neurotrophic factor can serve as a genuine ligand for Ret and can induce Ret-mediated formation of lamellipodia, cell surface protrusions that are implicated in neuritogenesis.

Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons.

It is demonstrated that NTN induces Ret phosphorylation in primary cultures of rat superior cervical ganglion (SCG) neurons, and data indicate that NTn is a physiologically relevant ligand for the Ret receptor and suggest thatNTN may have a critical role in the development of many neuronal populations.

Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins.

The isolation and characterization of rat and human cDNAs for a novel cell-surface associated accessory protein, RETL2, that shares 49% identity with RETL1 are reported, raising the possibility that RETL 1 andRETL2 have distinctive roles during development and in the nervous system of the adult.

Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130Cas mediated by Ret kinase

The results suggested the presence of Rho-dependent and -independent signaling pathways downstream of PI-3′ kinase that mediate tyrosine phosphorylation of FAK, paxillin and p130Cas through Ret kinase.

Grb2 binding to the different isoforms of Ret tyrosine kinase

It is concluded that in intact cells both Ret isoforms bind to Grb2, although with different modalities, in agreement with the possibility that different signal transduction pathways are associated with the two isoforms of Ret.

Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutation.

Findings suggested that high levels of activation of PI 3-kinase and of phosphorylation of its downstream signalling molecules may be associated with the clinical phenotype of MEN 2B.

Characterization of Ret-Shc-Grb2 complex induced by GDNF, MEN 2A, and MEN 2B mutations.

The results suggest that Ret dimerization might be required for binding of the Shc SH2 domain to the short isoform of MEN2A-Ret and in neuroblastoma cells expressing both isoforms of Ret, its activation by GDNF also resulted in the binding of both domains.

Receptors of the Glial Cell Line-Derived Neurotrophic Factor Family of Neurotrophic Factors Signal Cell Survival through the Phosphatidylinositol 3-Kinase Pathway in Spinal Cord Motoneurons

The ability of the GDNF family members to promote chicken motoneuron survival in culture is described and the ability of these factors to induce the phosphatidylinositol 3 kinase and the extracellular regulated kinase (ERK)–mitogen-activated protein (MAP) kinase pathways activation is demonstrated.