TY - JOUR
T1 - Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations
AU - Rossel, Mireille
AU - Pasini, Andrea
AU - Chappuis, Sophie
AU - Geneste, Olivier
AU - Fournier, Laurence
AU - Schuffenecker, Isabelle
AU - Takahashi, Masahide
AU - Van Grunsven, Leo A.
AU - Urdiales, José Luis
AU - Rudkin, Brian B.
AU - Lenoir, Gilbert M.
AU - Billaud, Marc
N1 - Funding Information:
We thank Dr V de Franciscis for sharing results prior to publication. We are grateful to Dr M Nagao for providing us with the pN6 cDNA; to Dr J Downward for the kind gift of the Ras N17-expressing PC12 cells; to Dr L Reichardt for the RTA antibody; to Dr M Chao for the anti-p75 antibody. We also thank Dr Hartmut Land for providing us with the pBabe Puro and pJ7O vectors. We wish to thank A Thomas for technical assistance, and Mrs Billaud, D Ydjedd and S Balter for the graphic work. This study was supported by the Ligue Nationale Contre le Cancer (Comités Départementaux de l’Ain et du Rhône), the ‘Fondation pour la Recherche Médicale’, the Association de la Recherche contre le Cancer. MR and AP are the recipients of a Fellowship from the Ligue Nationale contre le Cancer. SC and OG are the recipients of a Fellowship from the Ministry of Research and the Ligue Nationale Contre le Cancer, Comité Départemental de l’Indre, respectively. LAvG was supported by grants from the Ligue Nationale de Recherche Contre le Cancer, the Ministère des Affaires Etrangères, and Autodesk Development BV; JLU was supported by grants from Human Capital and Mobility Program from the European Union and from the Ligue National contre le Cancer, Comités Départementaux de l’Ain et de Saône et Loire. BBR is the coordinator of a Concerted Action Grant in Cancer Research BIOMED 1 (BMH1-CT94-1471) from the European Union and a cost-shared grant in Brain Research BIOMED 2 (BMHK4-CT96-0010).
PY - 1997
Y1 - 1997
N2 - Germline mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). MEN 2 mutations have been shown to result in RET oncogenic activation. The RET gene encodes several isoforms whose biological properties, when altered by MEN 2 mutations, have not been thoroughly addressed yet. In this study, we have introduced a MEN 2A mutation (Cys634 → Arg) and the unique MEN 2B mutation (Met918 → Thr) in two RET isoforms of 1114 and 1072 amino acids which differ in the carboxy-terminus part. Herein, we report that each RET isoform activated by MEN 2A or MEN 2B mutation was transforming in fibroblasts and induced neuronal differentiation of pheochromocytoma PC12 cells. However, among the different RET-MEN 2 mutants, the long RET isoform activated by the MEN 2B mutation stimulated the most prominent neurite outgrowth in PC12 cells, while the short RET isoform counterpart elicited a very weak differentiation effect in PC12 cells. We further demonstrate that the morphological changes of PC12 cells caused by constitutively activated RET oncoproteins involved the engagement of a Ras-dependent pathway. These findings provide evidence that the biological properties of RET-MEN 2 mutants depend on the interplay between the RET isoforms and the nature of the activating MEN 2 mutation.
AB - Germline mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). MEN 2 mutations have been shown to result in RET oncogenic activation. The RET gene encodes several isoforms whose biological properties, when altered by MEN 2 mutations, have not been thoroughly addressed yet. In this study, we have introduced a MEN 2A mutation (Cys634 → Arg) and the unique MEN 2B mutation (Met918 → Thr) in two RET isoforms of 1114 and 1072 amino acids which differ in the carboxy-terminus part. Herein, we report that each RET isoform activated by MEN 2A or MEN 2B mutation was transforming in fibroblasts and induced neuronal differentiation of pheochromocytoma PC12 cells. However, among the different RET-MEN 2 mutants, the long RET isoform activated by the MEN 2B mutation stimulated the most prominent neurite outgrowth in PC12 cells, while the short RET isoform counterpart elicited a very weak differentiation effect in PC12 cells. We further demonstrate that the morphological changes of PC12 cells caused by constitutively activated RET oncoproteins involved the engagement of a Ras-dependent pathway. These findings provide evidence that the biological properties of RET-MEN 2 mutants depend on the interplay between the RET isoforms and the nature of the activating MEN 2 mutation.
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U2 - 10.1038/sj.onc.1200831
DO - 10.1038/sj.onc.1200831
M3 - Article
C2 - 9018112
AN - SCOPUS:8044253411
SN - 0950-9232
VL - 14
SP - 265
EP - 275
JO - Oncogene
JF - Oncogene
IS - 3
ER -
