Single missense mutation in the tyrosine kinasecatalytic domain of the RET protooncogene is associated with multiple endocrineneoplasia type 2B.

Carlson, Katrin M.; Dou, Shenshen; Chi, David; Scavarda, Nancy; Toshima, Koji; Jackson, Charles E.; Wells, Samuel A.; Goodfellow, Paul J.; Donis-Keller, Helen

doi:10.1073/pnas.91.4.1579

Cited by 551 publications

(327 citation statements)

References 38 publications

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“…RET/PTC1, the one more frequently isolated, is generated by the fusion of RET to the 5'-terminal region of a gene designated H4 (Grieco et al, 1990). In addition, germline RET point mutations, responsible for the inheritance of the MEN2A (multiple endocrine neoplasia type 2A), MEN2B, and FTMC (familial medullary thyroid carcinoma) syndromes (Donis-Keller et al, 1993;Mulligan et al, 1993;Carlson et al, 1994;Hofstra et al, 1994), also lead to an activation of the transforming potential of RET Asai et al, 1995). In most of MEN2A and FMTC cases substitution of extracellular cysteines leads to a constitutive dimerization of the receptor Asai et al, 1995); in contrast, in the majority of MEN2B cases, a M918T mutation causes a change of Ret substrate speci®city Songyang et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

et al. 1998

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The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia type 2 syndromes. Inactivating mutations of RET have been associated to the congenital megacolon, i.e. Hirschprung's disease. In order to identify pathways that are relevant for Ret signalling to the nucleus, we have investigated its ability to induce the c-Jun NH 2 -terminal protein kinases (JNK). Here we show that triggering the endogenous Ret, expressed in PC12 cells, induces JNK activity; moreover, Ret is able to activate JNK either when transiently transfected in COS-1 cells or when stably expressed in NIH3T3 ®broblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Ret kinase function, as a kinase-de®cient RET mutant, associated with Hirschsprung's disease, fails to activate JNK. The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK: substitution of the tyrosine 1062 of Ret, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation. Experiments conducted with dominant negative mutants or with negative regulators demonstrate that JNK activation by Ret is mediated by Rho/Rac related small GTPases and, particularly, by Cdc42.

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Section: Introductionmentioning

confidence: 99%

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

et al. 1998

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“…Commonly, mutations in extracellular cysteine residues encoded by exons 10 and 11 of RET are associated with two inherited MTC syndromes, familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A (MEN 2A) (Donis-Keller et al, 1993;Mulligan et al, 1993). The predominant mutation in MEN 2B, a hereditary MTC syndrome more aggressive than MEN 2A, and in sporadic MTC, is a single missense mutation in exon 16 resulting in the replacement of a methionine with a threonine at codon 918 in the tyrosine kinase domain (Carlson et al, 1994;Eng et al, 1994;Hofstra et al, 1994.). These changes in the RET gene have been shown to be activating mutations leading to inappropriate kinase activity (Pasini et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells

et al. 1998

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Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the calcitonin secreting thyroid C-cells. Somatic and germline mutations in the RET proto-oncogene are associated with sporadic and inherited cases of MTC, respectively. The human MTC cell line, TT, can be di erentiated by activated raf-1. This di erentiation is characterized, in part, by down-regulation of the RET proto-oncogene. We now show that raf-1 induction is followed by activation of the downstream kinases MEK1/2 and ERK1/2 and that di erentiation is dependent on activation of MEK1/2. The concurrent down-regulation of RET appears to involve altered nuclear compartmentalization and transport of RET mRNA. Although RET is down-regulated during raf-1 mediated di erentiation, overexpression of activated RET alleles which resist down-regulation does not alter the raf-1 mediated di erentiation response. These data suggest that RET down-regulation is associated with, but not required, for raf-1 mediated MTC cell di erentiation and that the raf-1 signal transduction pathway plays a dominant role in promoting MTC cell di erentiation.

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“…Examples of activating mutations, directly a ecting the structure of the TK domain are those found in the tyrosine kinases Kit, Met and Ret, associated to human mast cell leukaemia and human mastocytosis (Longley et al, 1996), to HPRC (Human Papillary Renal Carcinoma; Schmidt et al, 1997) and to MEN2B (Multiple Endocrine Neoplasia type 2B; Carlson et al, 1994). These consist of the substitution of a conserved aspartic acid residue in subdomain VII of the kinase with a neutral residue (in Kit and Met) and of a methionine residue in subdomain VIII of the kinase into threonine (in Met and Ret).…”

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confidence: 99%

The Ron oncogenic activity induced by the MEN2B-like substitution overcomes the requirement for the multifunctional docking site

Santoro¹,

Penengo

Orecchia

et al. 2000

Oncogene

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Oncogenic activation of the Ron tyrosine kinase (Macrophage Stimulating Protein receptor) relies on substitutions of two highly conserved residues in the catalytic domain (D1232V and M1254T), which result in ligand-independent activation of the receptor, in vivo tumorigenesis and metastasis. We show here that the Y/F conversion of the Y 1317 residue in the kinase domain impairs tumorigenic and metastatic properties of Ron activated by the MEN2B-like mutation (Ron M1254T ), but not by other two oncogenic substitutions. Furthermore, Ron M1254T lacking the multifunctional docking site retains transforming and metastatic activity. These data reveal that the transforming activity of Ron M1254T mutant is dependent on Y 1317 phosphorylation, suggesting a shift in intramolecular substrate speci®city. Consistently, a shift of Ron M1254T kinase substrate speci®city was observed by in vitro peptide phosphorylation assays and in vivo receptor autophosphorylation. The Y 1317 phosphorylation elicits by itself activation of PI-3K/Akt and MAPK signalling pathways. Our data indicate that the accomplishment of the full oncogenic phenotype of Ron M1254T requires the phosphorylation both of the canonical C-terminal docking site and of the unique Y 1317 residue in the tyrosine kinase domain.

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Single missense mutation in the tyrosine kinasecatalytic domain of the RET protooncogene is associated with multiple endocrineneoplasia type 2B.

Cited by 551 publications

References 38 publications

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells

The Ron oncogenic activity induced by the MEN2B-like substitution overcomes the requirement for the multifunctional docking site

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