Signals for Receptor-Mediated Endocytosis

Abstract

Receptor-mediated endocytosis is the mechanism by which a variety of nutrients, hormones and growth factors are selectively removed from the circulation and rapidly taken up by cells (reviewed in Goldstein et al., 1985). Studies of the low density lipoprotein receptor (LDLR) provided the first evidence that the initial step in this process is the concentration of specific cell surface receptors in clathrin-coated pits (Anderson et al., 1977). Analysis of naturally-occurring internalization-defective mutant LDLRs from patients with familial hypercholesterolemia indicated that the cytoplasmic domain of the receptor was essential for high efficiency endocytosis. Mutant receptors from the patient J.D. differed from wild-type LDLR only by the substitution of a cysteine residue for tyrosine at position 807 within the cytoplasmic domain implying that this tyrosine was essential for rapid internalization (Davis et al., 1986). Subsequently, the cytoplasmic domains of other receptors including the transferrin receptor (TR) (Rothenberger et al., 1987; Jing et al., 1990), cation-independent mannose-6-phosphate receptor (Man-6-PR) (Lobel et al., 1989), polymeric immunoglobulin receptor (polyIgR) (Mostov et al., 1986) and asialoglycoprotein receptor (ASGPR) (Fuhrer et al., 1991) were shown to be important for clustering in coated pits and specific tyrosine residues within their cytoplasmic domains were also identified as critical for high efficiency endocytosis (Jing et al., 1990; Lobel et al., 1989; Breitfeld et al., 1990; Fuhrer et al., 1991). Together, these data led to the concept that constitutively recycling receptors have a tyrosine-containing internalization signal located within their cytoplasmic domains. However, the primary structures of receptor cytoplasmic tails were sufficiently dissimilar that inspection of their sequences did not reveal a shared feature that might provide a clue as to the nature of internalization signals and early attempts to identify internalization signals based on sequence patterns met with limited success (Vega and Strominger, 1989; Ktistakis et al., 1990). It was necessary, therefore, to determine the sequences of internalization signals of individual receptors experimentally by functional analysis of mutant receptors derived by in vitro mutagenesis. The internalization signals of several receptors have now been identified and, as described below, their properties can be accounted for by a model that invokes a common structural chemistry and implicates a tight et al. (1990), endocytosis. supported by direct structural have been substantiated and have led to further the properties of internalization signals that may have potential practical implications.