LAUSR

membrane, but rather undergoes constitutive internalization from the cell surface (1). Indeed, the endocytic kinetics for CFTR are remarkably fast, approaching that of nutrient receptors such as the LDL and transferrin receptors (2-4). Although there are several pathways for endocytic internalization, the evidence argues that CFTR is internalized exclusively through clathrin coated vesicles (3,5,6), with little, if any, CFTR entering through other clathrin independent pathways such as caveolae. Moreover, CFTR appears to enter the clathrin mediated endocytic pathway through a tyrosine-based endocytic motif located proximal to the carboxyl terminus (Y1424DSI) (7-9), which interacts directly with the mu2 subunit of the endocytic clathrin adaptor complex (AP2) (10) Ablation of either the endocytic signal in CFTR, or mutation of the tyrosine recognition sites on mu2 leads to an inhibition of CFTR endocytosis and a concomitant increase in cell surface CFTR. Once internalized, CFTR enters efficiently the endocytic recycling pathway, from whence it is trafficked back to the cell surface (11-14). Although a lot of effort has been expended to understand the endocytic traffic of wildtype CFTR, much less has been directed towards elucidating the endocytic trafficking pathways of mutant CFTR, particularly ∆F508 CFTR. This, in part, has been due to the low signal obtained with plasma membrane ∆F508 CFTR. Much attention has been directed towards manipulations that facilitate the exit of ∆F508 CFTR from the endoplasmic reticulum and its insertion into the plasma membrane. Indeed, pharmacological agents aimed at enhancing this process are the subject of intense research ay both academic and industrial laboratories. Until recently, the prevailing wisdom has been that getting ∆F508 CFTR to the cell surface will be sufficient to ameliorate or cure disease symptoms. Temperature corrected ∆F508 CFTR which reaches the plasma membrane has a significantly shorter half-live than wild-type CFTR (~6X less stable). This lowered stability is not due to enhanced endocytosis of ∆F508 CFTR, since the endocytic rates of wild-type and ∆F508 CFTR are similar. In contrast to the N287Y mutation which results in enhanced endocytosis of CFTR (15), ∆F508 CFTR does not get internalized any more rapidly than wild-type, arguing that initial endocytic events are not compromised in ∆F508 CFTR. However, in contrast to wildtype CFTR, once internalized, ∆F508 CFTR fails to enter the endocytic recycling pathway and does not colocalize with markers for the recycling pathway such as Rab11 or Rme-1, nor do purified recycling compartments contain ∆F508 CFTR. Such failure of ∆F508 CFTR to recycle necessitates an increase in the amount of ∆F508 CFTR which has to be pharmacologically “corrected” in order to compensate for the lack of recycling. However, it should be noted that studies so far argue that “temperature corrected” ∆F508 CFTR fails to enter the endocytic recycling pathway. Whether this is true for “pharmacologically corrected” ∆F508 CFTR remains to be determined.