Direct interactions among Ret, GDNF and GFRα1 molecules reveal new insights into the assembly of a functional three-protein complex

Amoresano, Angela; Incoronato, Mariarosaria; Monti, Gianluca; Pucci, Piero; Franciscis, Vittorio de; Cerchia, Laura

doi:10.1016/j.cellsig.2004.10.012

Cited by 42 publications

(31 citation statements)

References 25 publications

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“…To this aim, we used a specific competitive inhibitor of Ret activity consisting of the entire Ret wild-type extracellular domain in a soluble form, EC-Ret wt , which in the presence of GFRa1 protein sequesters GDNF, thus reducing the available ligand for the activation of the membrane-bound Ret receptor (17,18). As shown in Fig.…”

Section: Ra-induced Stimulation Of Ret and Erk Are Mediated By Gdnfmentioning

confidence: 99%

“…The entire Ret receptor extracellular portion (EC-Ret wt ) and the protein containing the first three NH 2 -terminal CLDs of EC-Ret wt but lacking CLD4 and CRD (named EC-Ret 1-387 ) were produced as reported previously (17,18). D4 is a 93-base 2 ¶-fluoro-RNA-based aptamer that specifically binds the extracellular domain of Ret thus interfering with ligand-induced stimulation of its intrinsic tyrosine kinase activity (19).…”

Section: Ret Inhibitorsmentioning

confidence: 99%

“…To minimize the contribution of TrkB, here, we chose to use the human SK-N-BE(2) neuroblastoma cell line (hereafter named SK-N-BE), in which RA-induced differentiation is preceded by a rapid accumulation of Ret but not of Trk family receptors that are not or poorly expressed (14,16). We used two specific interfering molecules to inhibit Ret function: the EC-Ret peptide that blocks Ret stimulation by competing for binding to the ligandGFRa complex (17,18) and the D4 aptamer that inhibits Ret activity by directly binding the receptor (19).…”

Section: Introductionmentioning

confidence: 99%

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An Autocrine Loop Involving Ret and Glial Cell–Derived Neurotrophic Factor Mediates Retinoic Acid–Induced Neuroblastoma Cell Differentiation

Cerchia

D’Alessio

Amabile

et al. 2006

Molecular Cancer Research

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Section: Ra-induced Stimulation Of Ret and Erk Are Mediated By Gdnfmentioning

confidence: 99%

Section: Ret Inhibitorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Autocrine Loop Involving Ret and Glial Cell–Derived Neurotrophic Factor Mediates Retinoic Acid–Induced Neuroblastoma Cell Differentiation

Cerchia

D’Alessio

Amabile

et al. 2006

Molecular Cancer Research

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“…1B). Previous experiments indicate that the GDNF-GFR␣1 complex binds directly to CLD4 and the cysteine-rich domain (53). This suggested that both RET ⌬E3 and RET ⌬E345 should be able to bind to the GDNF-GFR␣1 complex, and indeed this interaction was observed not only for GFR␣1 but also for GFR␣2, GFR␣3, and GFR␣4 (Fig.…”

Section: ⌬E3mentioning

confidence: 76%

“…It should be noted that, in our experiments, the chicken GFR␣4 construct contained all three cysteine-rich domains, unlike mammalian GFR␣4, which lacks domain 1. Although it was originally thought that CLD1-3 of RET was involved in direct binding from results obtained through mutagenesis studies, a direct interaction between CLD1-3 and the GDNF-GFR␣1 complex has not been observed (53,54). Instead, it has been proposed that CLD1-3 contributes to the stability of the tertiary structure of the GDNF-GFR␣1-RET complex by forming a secondary dimerization site to trap the GDNF-GFR␣1 binary complex (14).…”

Section: ⌬E3mentioning

confidence: 99%

Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction

Gabreski

Vaghasia

Novakova

et al. 2016

Journal of Biological Chemistry

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Rearranged during transfection (RET), a receptor tyrosine kinase that is activated by the glial cell line-derived neurotrophic factor family ligands (GFLs), plays a crucial role in the development and function of the nervous system and additionally is required for kidney development and spermatogenesis. RET encodes a transmembrane receptor that is 20 exons long and produces two known protein isoforms differing in C-terminal amino acid composition, referred to as RET9 and RET51. Studies of human pheochromocytomas identified two additional novel transcripts involving the skipping of exon 3 or exons 3, 4, and 5 and are referred to as RET ⌬E3 and RET ⌬E345 , respec- higher baseline autophosphorylation, specifically on the catalytic tyrosine, Tyr 905 , and also on one of the most important signaling residues, Tyr 1062 . These data provide the first evidence for a physiologic role of these isoforms in RET pathway function.RET is a receptor tyrosine kinase that is critical for kidney morphogenesis, spermatogenesis, and development of the nervous system (1-4). RET is activated by a family of four growth factors known as the glial cell line-derived neurotrophic factor (GDNF) 2 family ligands (GFLs), which includes GDNF, neurturin, artemin, and persephin (1). Each GFL binds to one of four cognate glycosylphosphatidylinositol-anchored co-receptors known as the GDNF family receptor ␣s (GFR␣s) (2, 5). The GFL-GFR␣ complex binds to RET, inducing RET dimerization and subsequent autophosphorylation on multiple tyrosine residues within the intracellular tyrosine kinase domain. This enhances tyrosine kinase activity and initiates the association of adaptor proteins and enzymes that trigger multiple second messenger cascades (6). The presence of two major Ret isoforms, RET9 and RET51, has been extensively described in the literature, and a third isoform, RET43, has also been observed in humans (7-9). Ret is 20 exons long, and Ret9 and Ret51 transcripts differ in alternative splicing of intron 19. Intron 19 in the Ret51 transcript is excised properly, whereas, in the Ret9 transcript, the intron is retained, changing the reading frame and inserting a premature stop codon into the amino acid sequence. This creates a unique nine-amino acid C-terminal sequence for RET9 and a unique 51-amino acid C-terminal sequence for RET51. Interestingly, these two different isoforms display marked differences in their degradation and function (7, 10, 11).Three additional Ret transcripts have been reported in various tumor sources as well as adult human tissues (12). These novel transcripts are a product of exon skipping in the 5Ј region of RET, which encodes for the extracellular domain of the protein. Skipping of exons 3 (RET ⌬E3 ) or exons 3, 4 and 5 (RET ⌬E345) gives rise to transcripts that encode for full-length Ret proteins but with deletions in the extracellular domain, specifically cadherin-like domain 1 (CLD1) or CLD1-3, respectively. These deletions are hypothesized to change the extracellular domain structure as well as binding to GFL-GFR...

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The RET Protooncogene

Traugott¹,

Moley

2009

Endocrine Neoplasia

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Direct interactions among Ret, GDNF and GFRα1 molecules reveal new insights into the assembly of a functional three-protein complex

Cited by 42 publications

References 25 publications

An Autocrine Loop Involving Ret and Glial Cell–Derived Neurotrophic Factor Mediates Retinoic Acid–Induced Neuroblastoma Cell Differentiation

An Autocrine Loop Involving Ret and Glial Cell–Derived Neurotrophic Factor Mediates Retinoic Acid–Induced Neuroblastoma Cell Differentiation

Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction

The RET Protooncogene

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