Characterization of the signal for rapid internalization of the bovine mannose 6-phosphate/insulin-like growth factor-II receptor.

570

773

The cation-independent mannose 6-phosphate receptor (CI-MPR) mediates sorting of lysosomal hydrolase precursors from the TGN to endosomes. After releasing the hydrolase precursors into the endosomal lumen, the unoccupied receptor returns to the TGN for further rounds of sorting. Here, we show that the mammalian retromer complex participates in this retrieval pathway. The hVps35 subunit of retromer interacts with the cytosolic domain of the CI-MPR. This interaction probably occurs in an endosomal compartment, where most of the retromer is localized. In particular, retromer is associated with tubular–vesicular profiles that emanate from early endosomes or from intermediates in the maturation from early to late endosomes. Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes. These observations indicate that retromer prevents the delivery of the CI-MPR to lysosomes, probably by sequestration into endosome-derived tubules from where the receptor returns to the TGN.

Section: Discussionmentioning

confidence: 93%

Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor

Arighi

Hartnell

Aguilar

et al. 2004

570

773

“…Tyr-dependent internalization signals in cellular proteins are functional when transferred to heterologous molecules, where their activity has been shown to be largely independent of position and orientation (Collawn et al, 1990; Collawn et al, 1991;Jadot et al, 1992). However, studies of the transferrin receptor YTRF signal have indicated that a critical distance of seven or more residues is required between the Tyr and the membrane spanning domain for optimal function (Collawn et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

An internalization signal in the simian immunodeficiency virus transmembrane protein cytoplasmic domain modulates expression of envelope glycoproteins on the cell surface.

Sauter

Pelchen–Matthews

Bron

et al. 1996

139

183

Abstract. A Tyr to Cys mutation at amino acid position 723 in the cytoplasmic domain of the simian immunodeficiency virus (sir) transmembrane (TM) molecule has been shown to increase expression of envelope glycoproteins on the surface of infected cells. Here we show that Tyr-723 contributes to a sorting signal that directs the rapid endocytosis of viral glycoproteins from the plasma membrane via coated pits. On ceils infected by SIVs with a Tyr at position 723, envelope glycoproteins were transiently expressed on the cell surface and then rapidly endocytosed. Similar findings were noted for envelope molecules expressed in the absence of other viral proteins. Immunoelectron microscopy demonstrated that these molecules were localized in patches on the cell surface and were frequently associated with coated pits. In contrast, envelope glycoproteins containing a Y723C mutation were diffusely distributed over the entire plasma membrane. To determine if an internalization signal was present in the SIV TM, chimeric molecules were constructed that contained the CD4 external and membrane spanning domains and a SIV TM cytoplasmic tail with a Tyr or other amino acids at SIV position 723. In Hela cells stably expressing these molecules, chimeras with a Tyr-723 were rapidly endocytosed, while chimeras containing other amino acids at position 723, including a Phe, were internalized at rates only slightly faster than a CD4 molecule that lacked a cytoplasmic domain. In addition, the biological effects of the internalization signal were evaluated on infectious viruses. A mutation that disrupted the signal and as a result, increased the level of viral envelope glycoprotein on infected cells, was associated with accelerated infection kinetics and increased cell fusion during viral replication. These resuits demonstrate that a Tyr-dependent motif in the SIV TM cytoplasmic domain can function as an internalization signal that can modulate expression of the viral envelope molecules on the cell surface and affect the biological properties of infectious viruses. The conservation of an analogous Tyr in all human and simian immunodeficiency viruses suggests that this signal may be present in other primate lentiviruses and could be important in the pathogenesis of these viruses in vivo.

“…Ligand-or single antibody-induced internalization of transmembrane proteins such as receptors requires an internalization motif in the cytoplasmic domain, which usually contains a critical tyrosine (Trowbridge, 1991). Such is the case in the transferrin receptor (Collawn et al, 1990;McGraw andMaxfield, 1990), LDL receptor (Chen et al, 1990;Bansal and Gierasch, 1991), marmose-6-phosphate receptor (Jadot et al, 1992), insulin receptor (Reynet et al, 1990;Rajagopalan et al, 1991), EGF receptor (Sorkin et al, 1992), and lysosomal acid phosphatase (Eberle et al, 1991;Lehmann et al, 1992). However, the cytoplasmic domain of the TGF-ct precursor (Derynck et al, 1984) does not contain a tyrosine residue which could be responsible for its internalization.…”

Section: Discussionmentioning

confidence: 99%

Association of the transmembrane TGF-alpha precursor with a protein kinase complex.

Shum

Reeves

Kuo

et al. 1994

Abstract, A variety of growth factors including transforming growth factor-c~ (TGF-o0 are synthesized as transmembrane precursors. The short cytoplasmic domain of the transmembrane TGF-ot precursor lacks any apparent motif associated with signal transduction. However, the sequence conservation of this cytoplasmic domain and its abundance of cysteine residues, reminiscent of the cytoplasmic domains of CD4 and CD8, suggest a biological function. In this study, we showed that transmembrane TGF-c~ was rapidly internalized after interaction with a specific antibody and that this internalization was greatly decreased when the COOH-terminal 31 amino acids were removed. Chemical cross-linking experiments revealed two associated proteins of 86 and 106 kD which coimmunoprecipitated with the TGF-cx precursor. The association of p86 was dependent on the presence of the COOH-terminal cytoplasmic 31 amino acids of the TGF-ot precursor, whereas p106 still remained associated when this segment was deleted. In addition, p106 was tyrosine-phosphorylated and exposed on the cell surface. The protein complex associated with transmembrane TGF-ot displayed kinase activities towards tyrosine, serine, and threonine residues. These activities were not associated with transmembrane TGF-c~ when the COOH-terminal segment was truncated. The association of a protein kinase complex with transmembrane TGF-cx may provide the basic elements for a "reverse" mode of signaling through the cytoplasmic domain of this growth factor, which may lead to two-directional communication during ligandreceptor interaction.