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Vol. 12, Issue 3, 675-684, March 2001
Receptor Endocytosis
and Intracellular Sorting Differ between Fibroblasts and Epithelial
Cells
Thoracic Diseases Research Unit and Department of Biochemistry and
Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905
Transforming growth factor-
s (TGF-) are multifunctional
proteins capable of either stimulating or inhibiting mitosis, depending on the cell type. These diverse cellular responses are caused by
stimulating a single receptor complex composed of type I and type II
receptors. Using a chimeric receptor model where the
granulocyte/monocyte colony-stimulating factor receptor ligand binding
domains are fused to the transmembrane and cytoplasmic signaling
domains of the TGF- type I and II receptors, we wished to describe
the role(s) of specific amino acid residues in regulating
ligand-mediated endocytosis and signaling in fibroblasts and epithelial
cells. Specific point mutations were introduced at Y182, T200, and Y249 of the type I receptor and K277 and P525 of the type II receptor. Mutation of either Y182 or Y249, residues within two putative consensus
tyrosine-based internalization motifs, had no effect on endocytosis or
signaling. This is in contrast to mutation of T200 to valine, which
resulted in ablation of signaling in both cell types, while only
abolishing receptor down-regulation in fibroblasts. Moreover, in the
absence of ligand, both fibroblasts and epithelial cells constitutively
internalize and recycle the TGF- receptor complex back to the plasma
membrane. The data indicate fundamental differences between mesenchymal
and epithelial cells in endocytic sorting and suggest that ligand
binding diverts heteromeric receptors from the default recycling pool
to a pathway mediating receptor down-regulation and signaling.
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