Abstract
The yeast a-factor receptor (Ste3p) is subject to two mechanistically distinct modes of endocytosis: a constitutive, ligand-independent pathway and a ligand-dependent uptake pathway. Whereas the constitutive pathway leads to degradation of the receptor in the vacuole, the present work finds that receptor internalized via the ligand-dependent pathway recycles. With the a-factor ligand continuously present in the culture medium, trafficking of the receptor achieves an equilibrium in which continuing uptake to endosomal compartments is balanced by its recycling return to the plasma membrane. Withdrawal of ligand from the medium leads to a net return of the internalized receptor back to the plasma membrane. Although recycling is demonstrated for receptors that lack the signal for constitutive endocytosis, evidence is provided indicating a participation of recycling in wild-type Ste3p trafficking as well: a-factor treatment both slows wild-type receptor turnover and results in receptor redistribution to intracellular endosomal compartments. Apparently, a-factor acts as a switch, diverting receptor from vacuole-directed endocytosis and degradation, to recycling. A model is presented for how the two Ste3p endocytic modes may collaborate to generate the polarized receptor distribution characteristic of mating cells.
Highlights
Recycling of cell surface receptors in mammalian cells allows the receptor protein to participate in multiple rounds of ligand binding and internalization (Ciechanover et al, 1983; Goldstein et al, 1985)
Rather than the vacuolar degradation associated with constitutive endocytosis, ligand-dependent uptake links instead to recycling: receptor internalized via this pathway to endosomal compartments recycles back to the cell surface
Ste3⌬365p stably accumulates at the plasma membrane
Summary
Recycling of cell surface receptors in mammalian cells allows the receptor protein to participate in multiple rounds of ligand binding and internalization (Ciechanover et al, 1983; Goldstein et al, 1985). In the yeast Saccharomyces cerevisiae, a number of plasma membrane proteins have been found to undergo a ubiquitin-dependent endocytosis that delivers the internalized protein to the vacuole (the yeast lysosome) for degradation (Bonifacino and Weissman, 1998; Hicke, 1999) Receptor recycling such as that described above for mammalian cells has yet to be observed in yeast, there is evidence for trafficking pathways that link endosomal compartments back to the cell surface. Ste3p constitutive uptake, but not ligand-dependent uptake requires two functions: the ankyrin-repeat protein Akr1p and the redundant Yck1p–Yck2p type I casein kinase pair (Givan and Sprague, 1997; Panek et al, 1997; Feng and Davis, 2000) These two functions act early in the constitutive uptake pathway, at a step before receptor ubiquitination, acting apparently for the phosphoryl activation of the PEST-like endocytosis signal (Feng and Davis, 2000). Rather than the vacuolar degradation associated with constitutive endocytosis, ligand-dependent uptake links instead to recycling: receptor internalized via this pathway to endosomal compartments recycles back to the cell surface
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