Journal of Cell Science, Vol 112, Issue 6 773-784, Copyright © 1999 by Company of Biologists

JOURNAL ARTICLES

The cytoplasmic carboxy-terminal amino acid determines the subcellular localization of proTGF-(alpha) and membrane type matrix metalloprotease (MT1-MMP)

JM Urena, A Merlos-Suarez, J Baselga and J Arribas
Laboratori de Recerca Oncologica, Servei d'Oncologia Medica, Hospital General Universitari Vall d'Hebron, Psg. Vall d'Hebron 119-129, Barcelona 08035, Spain.

Transforming growth factor alpha (TGF-(alpha)) is synthesized as a precursor transmembrane molecule (proTGF-(alpha)) whose ectodomain is shed from the cell surface generating mature, soluble, growth factor. In agreement with recent reports, here we show that the structural determinant that targets proTGF-(alpha) to the cell surface maps to the very C-terminal cytoplasmic amino acid, valine. The primary localization of proTGF-(alpha) C-terminal mutants is a perinuclear area that colocalizes with ER markers. Since the ectodomain shedding machinery that acts on proTGF-(alpha) is known to be located at the cell surface, deficient transport provides an explanation for the previously reported lack of PKC activated ectodomain shedding of proTGF-(alpha) C-terminal mutants. The transport of wild-type proTGF-(alpha) to the cell surface was found to be mediated by a mechanism that includes a specific component saturable by wild-type proTGF-(alpha) but not by cell surface transmembrane proteins whose trafficking is independent of their cytoplasmic tail such as betaglycan. C-terminal valines are likely to be a general determinant of the subcellular location of cell surface transmembrane proteins since the maturation and trafficking of MT1-MMP C-terminal mutants are severely impaired. Our data suggest the existence of a targeting mechanism that acts on cell surface transmembrane molecules as diverse as proTGF-(alpha) and MT1-MMP and that the interaction with such a mechanism depends on the identity of the C-terminal amino acid of the targeted molecules.

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