Expression and Alternative Splicing of Mouse Gfra4 Suggest Roles in Endocrine Cell Development

Lindahl, Maria; Timmusk, Tõnis; Rossi, Jari; Saarma, Märt; Airaksinen, Matti S.

doi:10.1006/mcne.2000.0845

Cited by 89 publications

(93 citation statements)

References 27 publications

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“…After we discovered that this novel GFR␣ was a high affinity coreceptor for persephin, we renamed it GFR␣-4 in order to comply with established GFR␣ nomenclature (8). During the preparation of this manuscript, a mouse GFR␣-4 receptor equivalent to the one described in this paper was reported (43). The high divergence of the mammalian GFR␣-4 from the avian orthologue is remarkable, since the similarity of mammalian GFR␣-1 and GFR␣-2 to their chicken counterparts is much higher (e.g.…”

Section: Discussionmentioning

confidence: 99%

Mammalian GFRα-4, a Divergent Member of the GFRα Family of Coreceptors for Glial Cell Line-derived Neurotrophic Factor Family Ligands, Is a Receptor for the Neurotrophic Factor Persephin

Masure¹,

Cik²,

Hoefnagel³

et al. 2000

Journal of Biological Chemistry

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Four members of the glial cell line-derived neurotrophic factor family have been identified (GDNF, neurturin, persephin, and enovin/artemin). They bind to a specific membrane-anchored GDNF family receptor as follows: GFR␣-1 for GDNF, GFR␣-2 for neurturin, GFR␣-3 for enovin/artemin, and (chicken) GFR␣-4 for persephin. Subsequent signaling occurs through activation of a common transmembrane tyrosine kinase, cRET. GFR␣-4, the coreceptor for persephin, was previously identified in chicken only. We describe the cloning and characterization of a mammalian persephin receptor GFR␣-4. The novel GFR␣ receptor is substantially different in sequence from all known GFR␣s, including chicken GFR␣-4, and lacks the first cysteine-rich domain present in all previously characterized GFR␣s. At least two different GFR␣-4 splice variants exist in rat tissues, differing at their respective COOH termini. GFR␣-4 mRNA is expressed at low levels in different brain areas in the adult as well as in some peripheral tissues including testis and heart. Recombinant rat GFR␣-4 variants were expressed in mammalian cells and shown to be at least partially secreted from the cells. Persephin binds specifically and with high affinity (K D ‫؍‬ 6 nM) to the rat GFR␣-4 receptor, but no cRET activation could be demonstrated. Although the newly characterized mammalian GFR␣-4 receptor is structurally divergent from previously characterized GFR␣ family members, we suggest that it is a mammalian orthologue of the chicken persephin receptor. This discovery will allow a more detailed investigation of the biological targets of persephin action and its potential involvement in diseases of the nervous system.

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Section: Discussionmentioning

confidence: 99%

Mammalian GFRα-4, a Divergent Member of the GFRα Family of Coreceptors for Glial Cell Line-derived Neurotrophic Factor Family Ligands, Is a Receptor for the Neurotrophic Factor Persephin

Masure¹,

Cik²,

Hoefnagel³

et al. 2000

Journal of Biological Chemistry

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“…Glycerophosphatidylinositol-anchored coreceptors, termed the GFR␣ coreceptors, act as the high-affinity binding proteins of the GFLs. This GFL-GFR␣ complex then associates with Ret and activates it (Baloh et al, 1997(Baloh et al, , 1998aBuj-Bello et al, 1997;Klein et al, 1997;Cacalano et al, 1998;Enokido et al, 1998;Lindahl et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

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The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are critical for nervous system development and maintenance. GFLs promote survival and growth via activation of the receptor tyrosine kinase (RTK) Ret. In sympathetic neurons, the duration of Ret signaling is governed by how rapidly Ret is degraded after its activation. In an effort to elucidate mechanisms that control the half-life of Ret, we have identified two novel Ret interactors, CD2-associated protein (CD2AP) and Cbl-3. CD2AP, an adaptor molecule involved in the internalization of ubiquitinated RTKs, is associated with Ret under basal, unstimulated conditions in neurons. After Ret activation by GDNF, CD2AP dissociates. Similarly, the E3-ligase Cbl-3 interacts with unphosphorylated Ret and dissociates from Ret after Ret activation. In contrast to their dissociation from autophosphorylated Ret, an interaction between CD2AP and Cbl-3 is induced by GDNF stimulation of sympathetic neurons, suggesting that CD2AP and Cbl-3 dissociate from Ret as a complex. In neurons, the overexpression of CD2AP enhances the degradation of Ret and inhibits GDNF-dependent survival, and gene silencing of CD2AP blocks Ret degradation and promotes GDNF-mediated survival. Surprisingly, Cbl-3 overexpression dramatically stabilizes activated Ret and enhances neuronal survival, even though Cbl-family E3 ligases normally function to trigger RTK downregulation. In combination with CD2AP, however, Cbl-3 promotes Ret degradation rapidly and almost completely blocks survival promotion by GDNF, suggesting that Cbl-3 acts as a switch that is triggered by CD2AP and oscillates between inhibition and promotion of Ret degradation. Consistent with the hypothesis, Cbl-3 silencing in neurons only inhibited Ret degradation and enhanced neuronal survival in combination with CD2AP silencing. CD2AP and Cbl-3, therefore, constitute a checkpoint that controls the extent of Ret downregulation and, thereby, the sensitivity of neurons to GFLs.

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“…Physiologically, RET, GFRa4, and persephin appear to be necessary for migration of neural crest calcitonin producing cells into the developing thyroid gland: markedly diminished parafollicular C cells are found in RET K/K mice (Lindahl et al 2000, Lindfors et al 2006.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism

Borrello¹,

Aiello²,

Peissel³

et al. 2011

Endocrine-Related Cancer

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Activating mutations of RET, a gene encoding two isoforms of a tyrosine kinase receptor physiologically expressed in several neural crest-derived cell lineages, are associated with the inherited forms of medullary thyroid carcinoma (MTC). The identification and characterization of novel RET mutations involved in MTC is valuable, as RET gene testing plays a crucial role in the management of these patients. In an MTC patient, we have identified a germline c.1996AOG transition in heterozygosis leading to K666E substitution. In addition, the conservative S904S (c.2712COG) and the non-conservative functional G691S (c.2071GOA) polymorphisms have been identified. Through functional studies, we demonstrate for the first time that K666E is a gain-of-function mutation with oncogenic potential, based on its ability to transform NIH3T3 cells. It was not possible to define whether K666E is a de novo or inherited RET variant in the patient, as the family history was negative for MTC, and the carrier status of family members could not be tested. Our results, together with a recent report of co-segregation of the mutation in three MTC families, suggest that K666E is a causative MTC mutation. As we have shown that the same patient allele carries both K666E and G691S variants, the latter known to increase downstream RET signaling, a possible role for the G691S polymorphism has also been investigated. We have demonstrated that, although RET-G691S is not oncogenic per se, it enhances the transforming activity of the RET-K666E mutant, thus suggesting a modifier role for this functional polymorphism.

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Expression and Alternative Splicing of Mouse Gfra4 Suggest Roles in Endocrine Cell Development

Cited by 89 publications

References 27 publications

Mammalian GFRα-4, a Divergent Member of the GFRα Family of Coreceptors for Glial Cell Line-derived Neurotrophic Factor Family Ligands, Is a Receptor for the Neurotrophic Factor Persephin

Mammalian GFRα-4, a Divergent Member of the GFRα Family of Coreceptors for Glial Cell Line-derived Neurotrophic Factor Family Ligands, Is a Receptor for the Neurotrophic Factor Persephin

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism

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