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Molecular and Cellular Biology, October 2001, p. 6719-6730, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6719-6730.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Sensitivity of Activated Cys Ret Mutants to Glial Cell Line-Derived Neurotrophic Factor Is Mandatory To Rescue Neuroectodermic Cells from Apoptosis

Baharia Mograbi,1,dagger Renata Bocciardi,1,2 Isabelle Bourget,1 Thierry Juhel,1 Dariush Farahi-Far,1 Giovanni Romeo,3 Isabella Ceccherini,2 and Bernard Rossi1,*

INSERM U 364, IFR50, Faculté de Médecine Pasteur, Nice,1 and Unit of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon,3 France, and Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genoa, Italy2

Received 31 January 2001/Returned for modification 13 March 2001/Accepted 30 June 2001

Hirschsprung's disease (HSCR), a frequent developmental defect of the enteric nervous system is due to loss-of-function mutations of RET, a receptor tyrosine kinase essential for the mediation of glial cell-derived neurotrophic factor (GDNF)-induced cell survival. Instead, gain-of-function Cys mutations (e.g., Cys609, Cys620, and Cys634) of the same gene are responsible for thyroid carcinoma (MEN2A/familial medullary thyroid carcinoma) by causing a covalent Ret dimerization, leading to ligand-independent activation of its tyrosine kinase. In this context, the association of Cys609- or Cys620-activating mutations with HSCR is still an unresolved paradox. To address this issue, we have compared these two mutants with the Cys634 Ret variant, which has never been associated with HSCR, for their ability to rescue neuroectodermic cells (SK-N-MC cells) from apoptosis. We show here that despite their constitutively activated kinase, the mere expression of these three mutants does not allow cell rescue. Instead, we demonstrate that like the wild-type Ret, the Cys634 Ret variant can trigger antiapoptotic pathways only in response to GDNF. In contrast, Cys609 or Cys620 mutations, which impair the terminal Ret glycosylation required for its insertion at the plasma membrane, abrogate GDNF-induced cell rescue. Taken together, these data support the idea that sensitivity to GDNF is the mandatory condition, even for constitutively activated Ret mutants, to rescue neuroectodermic cells from apoptosis. These findings may help clarify how a gain-of-function mutation can be associated with a developmental defect.

* Corresponding author. Mailing address: INSERM U 364, Faculté de Médecine Pasteur, Ave. de Valombrose, 06107 Nice Cedex 02, France. Phone: 33 04 93 37 77 02. Fax: 33 04 93 81 94 56. E-mail: rossi{at}unice.fr.

dagger Present address: EMI 00-09, IFR50, Faculté de Médecine Pasteur, Nice, France.

Molecular and Cellular Biology, October 2001, p. 6719-6730, Vol. 21, No. 20
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.20.6719-6730.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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