Open AccessTransferrin Receptor Functions as a Signal‐Transduction Molecule for its Own Recycling Via Increases in the Internal Ca 2 Concentration
Author(s) -
SainteMarie Josette,
Lafont Virginie,
Pécheur EveIsabelle,
Favero Jean,
Philippot Jean R.,
Bienvenüe Alain
Publication year - 1997
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1997.00689.x
Subject(s) - internalization , receptor , transferrin receptor , calmodulin , transferrin , second messenger system , egta , jurkat cells , chemistry , ligand (biochemistry) , signal transduction , microbiology and biotechnology , biochemistry , biophysics , calcium , biology , t cell , enzyme , immunology , immune system , organic chemistry
Transferrin binding to its receptor modulates transferrin receptor (Tf‐R) recycling rates in several cells [Klausner, R. D., Van Renswoude, J., Ashwell, G., Kempf, C., Schechter, A., Dean, A. & Bridges, K. R. (1983a) J. Biol. Chem. 258 , 4715–4724; Gironès, N. & Davis, R. J. (1989) Biochem. J. 264 , 35–46; Sainte‐Marie, J., Vidal, M., Bette‐Bobillo, P., Philippot, J. R. & Bienvenüe, A. (1991) Eur. J. Biochem. 201 , 295–302]. To delineate the mechanism of this regulation, we hypothesized that the binding of the ligand to its receptor could lead to activation of several second‐messenger pathways, which may redundantly stimulate recycling of the receptor. The effects of different regulators of Ca 2 flux or concentrations were investigated on the Tf‐R–recycling pathway; these studies were carried out in two cell types. Perhexiline, a calcium antagonist, slowed receptor recycling in comparison with the control by more than 80% in L 2 C cells and by 60% in Jurkat cells (B and T lymphoblasts, respectively) but did not affect their internalization rate. Perhexiline thus trapped considerable amounts of Tf‐R in the internal compartment. Ca 2 chelators, such as EGTA or 1,2‐bis(2‐aminophenoxy)ethane‐ N,N,N,N′ ‐tetraacetic acid, and a Ca 2 ‐channel inhibitor (Ni 2 ) decreased drastically the recycling rate of Tf‐R. Tf‐R recycling was shown to be slowed by a calmodulin antagonist. Conversely, artificial elevation of free internal Ca 2 in L 2 C cells, using lectin, accelerated the recycling rate. These results suggest that the intracellular Ca 2 concentration plays an important role in the outward flow of transferrin receptors. Consequently, we examined the role of transferrin in internal free Ca 2 regulation. The addition of transferrin or anti‐(Tf‐R) Ig specifically elicited a rise in [Ca 2 ], as demonstrated by inefficacy of apotransferrin or irrelevant antibodies. These results suggest that Ca 2 is a regulator of Tf‐R recycling and that Tf‐R seems to function as a signal‐transduction molecule (perhaps in conjunction with other membrane proteins) rather than merely as an endocytic receptor.