This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 18/4/1004    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arighi, E. Articles by Sariola, H. Search for Related Content PubMed PubMed Citation Articles by Arighi, E. Articles by Sariola, H.

Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung’s Disease

Developmental Biology (E.A., A.P., N.M.P., H.S.), Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland FIN-00014; Department of Experimental Oncology (E.A., D.D., M.G.B., C.C., M.A.P.), Istituto Nazionale Tumori, 20133 Milan, Italy; and Helsinki University Central Hospital (HUCH) Laboratory Diagnostics (H.S.), Paediatric Pathology, HUCH, Helsinki, Finland FIN-00029

Address all correspondence and requests for reprints to: Hannu Sariola, Developmental Biology, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, University of Helsinki, Helsinki, Finland FIN-00014. 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, 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. Loss-of-function mutations of ret cause Hirschsprung’s disease (HSCR) or colonic aganglionosis. In 20–30% of families with a mutation at residues 609, 611, 618, or 620 of RET, MEN 2A and familial medullary thyroid carcinoma cosegregate 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 Madin-Darby canine kidney (MDCK) cells, the Janus mutation impairs the glial cell line-derived neurotrophic factor-induced effects of RET on cell migration, differentiation, and survival but simultaneously promotes rapid cell proliferation.

This article has been cited by other articles:

				T. S. Gujral, V. K. Singh, Z. Jia, and L. M. Mulligan Molecular Mechanisms of RET Receptor-Mediated Oncogenesis in Multiple Endocrine Neoplasia 2B. Cancer Res., November 15, 2006; 66(22): 10741 - 10749. [Abstract] [Full Text] [PDF]

				J. W. B. de Groot, T. P. Links, J. T. M. Plukker, C. J. M. Lips, and R. M. W. Hofstra RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors Endocr. Rev., August 1, 2006; 27(5): 535 - 560. [Abstract] [Full Text] [PDF]

				C. Carniti, S. Belluco, E. Riccardi, A. N. Cranston, P. Mondellini, B. A.J. Ponder, E. Scanziani, M. A. Pierotti, and I. Bongarzone The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung's Disease Am. J. Pathol., April 1, 2006; 168(4): 1262 - 1275. [Abstract] [Full Text] [PDF]

				G. Gamba Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension Am J Physiol Renal Physiol, February 1, 2005; 288(2): F245 - F252. [Abstract] [Full Text] [PDF]