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This version published online on January 8, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0173
Molecular Endocrinology Vol. 0, No. 2004 200301731-
doi:10.1210/me.2003-0173
Copyright © 2004 by the Endocrine Society.
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Submitted on May 12, 2003
Accepted on December 31, 2003

Biological effects of the dual phenotypic Janus mutation of ret co-segregating with both multiple endocrine neoplasia type 2 and Hirschsprung's disease

Elena Arighi, Anna Popsueva, Debora Degl'Innocenti, Maria Grazia Borrello, Cristiana Carniti, Nina M. Perälä, Marco A. Pierotti, and Hannu Sariola*

Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, FIN-00014 University of Helsinki, Finland; Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy; HUCH Laboratory Diagnostics, Paediatric Pathology, P.O. Box 400, FIN-00029 Helsinki University Central Hospital, Finland

* To whom correspondence should be addressed. E-mail: Hannu.Sariola{at}helsinki.fi.

Gain-of-function mutations of ret receptor tyrosine kinase, the signaling receptor for glial cell line-derived neurotrophic factor (GDNF), cause sporadic thyroid and adrenal malignancies as well as endocrine cancer syndromes, such as multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC). Loss-of-function mutations of ret cause Hirschsprung's disease (HSCR) or colonic aganglionosis. In 20 to 30% of families with a mutation at the residues 609, 611, 618 or 620 of ret, MEN 2A and FMTC co-segregate with HSCR. These mutations constitutively activate RET due to aberrant disulfide homodimerization and diminish the level of RET at the plasma membrane. It is not known how these mutations simultaneously lead to both gain- and loss-of-function RET-associated diseases. We provide an explanation for the dual phenotypic "Janus" mutation at Cys620 of ret. In MDCK cells, the Janus mutation impairs the GDNF-induced effects of RET on cell migration, differentiation and survival, but simultaneously promotes rapid cell proliferation.
Key words: MEN 2 • FMTC • HSCR • GDNF • MDCK




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