Differential interaction of Enigma protein with the two RET isoforms

Borrello, Maria Grazia; Mercalli, Elena; Perego, Carla; Degl’Innocenti, Debora; Ghizzoni, Simona; Arighi, Elena; Eroini, Barbara; Rizzetti, Maria Grazia

doi:10.1016/s0006-291x(02)00886-0

Cited by 33 publications

(21 citation statements)

References 39 publications

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“…The Tyr1062 is indeed only two residues amino-terminal to the C-terminal RET splice site, which thus alters the context of this residue between the two isoforms. Consistent with this, Tyr1062 multidocking site in short and long isoforms does appear to have differential interactions with SHC and ENIGMA proteins (Lorenzo et al, 1997;Borrello et al, 2002). Consequently, the Tyr1062 of the short isoform might be able to selectively activate unidentified transducers, possibly different from GRB2, which are required to induce cell-branching activity.…”

Section: Tyr1062 Differentially Required By Two Ret Isoforms D Degl'imentioning

confidence: 61%

“…Anti-Ret common I and II rabbit polyclonal antibodies were developed, respectively, against the 1011-1027 and 1000-1014 amino acids of the C-terminal sequence common to the two RET isoforms, as previously described (Borrello et al, 2002). Anti-phosphoTyrosine (anti-pTyr) monoclonal antibody and anti-Shc polyclonal antibodies were purchased from Upstate Biotechnology, Anti-Akt, anti-phospho(Ser473)Akt, antiErk1/2, anti-phospho(Thr202/Tyr204)Erk1/2 and anti-p38 antibodies were purchased from Cell Signaling.…”

Section: Antibodiesmentioning

confidence: 99%

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Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

et al. 2004

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Section: Tyr1062 Differentially Required By Two Ret Isoforms D Degl'imentioning

confidence: 61%

Section: Antibodiesmentioning

confidence: 99%

Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

et al. 2004

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“…Alternatively, it is possible that other proteins that also bind to the Y1062 region of Ret9 and Ret51 could in principle mediate some of the functional differences of the Ret isoforms. Among them is the PDZ-LIM protein Enigma which binds to the Y1062 area of Ret9 in a phosphorylation-independent manner (7,14,15) and requires the sequence R1064 I1065 S1066, which is absent in Ret51. Therefore, our Ret 51-RI allele is unsuitable to test conclusively the potential role of Enigma in the differential activities of Ret isoforms.…”

Section: Discussionmentioning

confidence: 99%

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

Wong

Bogni²,

Kotka

et al. 2005

Molecular and Cellular Biology

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The receptor tyrosine kinase Ret plays a critical role in the development of the mammalian excretory and enteric nervous systems. Differential splicing of the primary Ret transcript results in the generation of two main isoforms, Ret9 and Ret51, whose C-terminal amino acid tails diverge after tyrosine (Y) 1062. Monoisoformic mice expressing only Ret9 develop normally and are healthy and fertile. In contrast, animals expressing only Ret51 have aganglionosis of the distal gut and hypoplastic kidneys. By generating monoisoformic mice in which Y1062 of Ret9 has been mutated to phenylalanine, we demonstrate that this amino acid has a critical role in Ret9 signaling that is necessary for the development of the kidneys and the enteric nervous system. These findings argue that the distinct activities of Ret9 and Ret51 result from the differential regulation of Y1062 by C-terminal flanking sequences. However, a mutation which places Y1062 of Ret51 in a Ret9 context improves only marginally the ability of Ret51 to support renal and enteric nervous system development. Finally, monoisoformic mice expressing a variant of Ret9 in which a C-terminal PDZ-binding motif was mutated develop normally and are healthy. Our studies identify Y1062 as a critical regulator of Ret9 signaling and suggest that Ret51-specific motifs are likely to inhibit the activity of this isoform.

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“…G418 selection was also performed to normalize the results. Both isoforms of RET were tested, as we have demonstrated that long isoforms of oncogenic RETs display a stronger transforming activity compared with the short ones (Borrello et al 2002), thus enhancing the possibility of identifying mild activating mutations. The results of three transfections, performed in triplicate and normalized on the number of NIH3T3 G418-resistant colonies, are shown in Fig.…”

Section: Resultsmentioning

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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Differential interaction of Enigma protein with the two RET isoforms

Cited by 33 publications

References 39 publications

Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching

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

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

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