Molecular heterogeneity of RET loss of function in Hirschsprung's disease - PubMed (original) (raw)

. 1996 Jun 3;15(11):2717-25.

Affiliations

Molecular heterogeneity of RET loss of function in Hirschsprung's disease

F Carlomagno et al. EMBO J. 1996.

Abstract

The RET proto-oncogene encodes a receptor with tyrosine kinase activity (RET) that is involved in several neoplastic and non-neoplastic diseases. Oncogenic activation of RET, achieved by different mechanisms, is detected in a sizeable fraction of human thyroid tumors, as well as in multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinoma tumoral syndromes. Germline mutations of RET have also been associated with a non-neoplastic disease, the congenital colonic aganglionosis, i.e. Hirschsprung's disease (HSCR). To analyse the impact of HSCR mutations on RET function, we have introduced into wild-type RET and activated RET(MEN2A) and RET(MEN2B) alleles three missense mutations associated with HSCR. Here we show that the three mutations caused a loss of function of RET when assayed in two model cell systems, NIH 3T3 and PC12 cells. The effect of different HSCR mutations was due to different molecular mechanisms. The HSCR972 (Arg972-->Gly) mutation, mapping in the intracytoplasmic region of RET, impaired its tyrosine kinase activity, while two extracellular mutations, HSCR32 (Ser32-->Leu) and HSCR393 (Phe393-->Leu), inhibited the biological activity of RET by impairing the correct maturation of the RET protein and its transport to the cell surface.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Science. 1987 Jul 10;237(4811):178-82 - PubMed
    1. Science. 1987 Nov 6;238(4828):797-9 - PubMed
    1. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4691-5 - PubMed
    1. Science. 1988 Jul 1;241(4861):42-52 - PubMed
    1. Gene. 1989 Aug 15;80(2):325-36 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources