Co-migration and internalization of transferrin and its receptor on K562 cells.

Enns, Caroline A.; Larrick, James W.; Suomalainen, H. A.; Schröder, Jim; Sussman, Howard H.

doi:10.1083/jcb.97.2.579

Cited by 84 publications

(37 citation statements)

References 21 publications

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“…In addition, because transferrin is thought not to dissociate from its receptor inside the cell (18,19), the pathway of recycling of transferrin might provide invaluable morphologic clues to the pathway(s) of receptor recycling. Consistent with previous studies in our laboratory and others, transferrin enters cells via coated pits and receptosomes (10,11,(20)(21)(22)(23)(24). Transferrin is then detected in tubules of the TRG and, a short time later, in structures with an appearance similar to the tubules of the TRG, but intimately associated with microtubules.…”

supporting

confidence: 76%

Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells.

Willingham¹,

Hanover²,

Dickson³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

180

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The pathway of transferrin uptake and recycling was investigated in KB cells to attempt to identify the organelles involved in the return of transferrin to the cell surface. Comparison was made with the pathway of internalization of epidermal growth factor (EGF), which has been shown to terminate in lysosomes. A horseradish peroxidase coIjugate of transferrin (TF-HRP) was incubated with KB cells at 40C and, at various times after warming to 370C, the location of TF-HRP was examined at the electron microscopic level. Transferrin, like EGF, was found to enter cells via coated pits and to move to the Golgi region in receptosomes (endosomes). Transferrin was located in the tubular elements of the transreticular portion of the Golgi but not in Golgi stacks. Interestingly, transferrin was not concentrated in the coated pits of the Golgi. In contrast, EGF was highly concentrated there. Transferrin was next detected in tubular elements (=600 A in width and up to 5,000 A in length) that were closely associated with microtubules and in dumbbell-shaped structures. In contrast, EGF was not detected in these structures. These results suggest that those organelles containing transferrin, but not EGF, participate in the return of receptor-bound transferrin to the cell surface.The entry of many ligands into cells by receptor-mediated endocytosis has been characterized by using both morphological and biochemical methods (1, 2). In most of these studies, ligand bound to a surface receptor can be found in clathrin-coated pits at the cell surface within seconds to minutes after binding to a surface receptor. After less than another minute, the ligand is found in intracellular endocytic vesicles termed receptosomes (or endosomes) (3-5). Receptosomes are acidic vesicles (6) that move by saltatory motion (1, 3). They have been shown to carry ligands such as epidermal growth factor (EGF) (7) and 0-galactosidase (8) from the cell surface to the cell interior, where they were delivered into the transreticular elements of the Golgi system (TRG). From the TRG these ligands and presumably many others are transferred to lysosomes, where they can be degraded (1, 2).Previous studies from our laboratory have presented data on the entry of EGF into KB cells using a covalent conjugate of EGF with horseradish peroxidase (EGF-HRP) (7, 9). After entry through coated pits the ligand was found first in receptosomes and then in the TRG. There it became concentrated in the small clathrin-coated pits of the TRG prior to its delivery to lysosomes. The suggestion was made that the role of these small coated pits of the TRG might be to segregate and concentrate those materials destined for delivery to lysosomes.The current study examines the pathway of transferrin entry and compares it with the pathway followed by EGF (7,9). Transferrin is of particular interest because after releasing its iron into the cell, it is returned intact to the extracellular medium instead of being directed to lysosomes like EGF (10-17). Thus, by comparing the intracellula...

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supporting

confidence: 76%

Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells.

Willingham¹,

Hanover²,

Dickson³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

180

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“…However, our data suggest that receptor capping is not a general mechanism, because TfR capping (ref. 29 and Fig. 8 A, which is published as supporting information on the PNAS web site) does not alter polarity (Figs.…”

Section: Discussionmentioning

confidence: 99%

Ligation of the cell surface receptor, CD46, alters T cell polarity and response to antigen presentation

Oliaro

Pasam

Waterhouse

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Lymphocyte function in vivo is dictated by multiple external cues, but the integration of different signals is not well understood. Here, we show that competition for the axis of polarization dictates functional outcomes. We investigated the effect of ligation of the immunoregulatory cell surface receptor, CD46, on lymphocyte polarity during antigen presentation and cytotoxic effector function. Ligation of CD46 on human T cells prevented recruitment of the microtubule organizing center, CD3, and perforin to the interface with the antigen-presenting cell and caused a reduction in IFN-␥ production. In human NK cells, similar changes in polarity induced by CD46 ligation inhibited the recruitment of the microtubule organizing center and perforin to the interface with target cells and correlated with reduced killing. These data indicate that external signals can alter lymphocyte polarization toward antigen-presenting cells or target cells, inhibiting lymphocyte function.immunological synapse ͉ measles ͉ polar axis ͉ T cell signaling ͉ cytotoxicity L ymphocyte function is inf luenced by multiple extracellular cues, and the response to these signals is regulated by compartmentalization of proteins into distinct domains within the cell, for instance during migration or antigen presentation (1-3). Antigen presentation involves the formation of an immunological synapse (IS) proximal to the antigenpresenting cell (APC), remodeling of the actin and tubulin cytoskeletal networks, and clustering of signaling complexes at the distal pole of an axis perpendicular to the APC (4). Intracellular compartmentalization can control the sensitivity to signal, the duration of responsiveness to signal, and the direction of effector responses such as migration, cytotoxicity, and cytokine secretion (5). The signals that trigger polarization, such as ligation of chemokine receptors or the T cell receptor (TCR), are often modulated by the ensuing polarization state (2, 5), suggesting that cell polarity provides an inbuilt feedback mechanism.Recent reports suggest that extracellular signals compete to dictate both lymphocyte polarity and functional outcome. The intensity of signal from two target cells attached to the same T cell dictates the polarization of cytolytic granules (6). Competition between TCR and chemokine signaling determines whether a T cell adopts migratory polarization or forms an IS (7-9). To explore whether competition for polarization might provide a general means for controlling lymphocyte function, we investigated the effects of a competing polarizing signal on the response of lymphocytes to TCR or NK receptor signaling.CD46 is a cell surface receptor for complement C3b and a number of pathogens, including measles viruses (10 -12). CD46 ligation has been proposed to limit acquired immune function in response to complement and pathogens (12, 13) and facilitate the dramatic immunosuppression triggered by measles infection (14). Indeed, ligation of CD46 can mediate direct effects on T cell function, such as inducing regulat...

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“…Like the transferrin and EGF-receptor complexes (25,26,31), the 125 I-hCG-LHR complex remains associated during internalization (7,9), and internalization of the complex can be conveniently assessed by following the distribution of the bound 125 I-hCG between the cell surface and the interior of the cell (see "Materials and Methods"). The results presented in Table I show that grafting only the Cterminal domain of the rLHR onto the hLHR (i.e.…”

Section: Signaling Properties and Internalization Of Hcg Mediated By mentioning

confidence: 99%

Seven Non-contiguous Intracellular Residues of the Lutropin/Choriogonadotropin Receptor Dictate the Rate of Agonist-induced Internalization and Its Sensitivity to Non-visual Arrestins

Nakamura¹,

Liu

Ascoli

2000

Journal of Biological Chemistry

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The amino acid sequences of the human (h) and rat (r) lutropin/choriogonadotropin receptors (LHR) are 87% identical, but the rate of agonist-induced internalization of the hLHR is ϳ7 times faster than that of the rLHR. Chimeras of the hLHR and the rLHR showed that this rate is dictated by the serpentine domain and the cytoplasmic tail. Further mutational analysis identified seven residues, two adjacent residues in the second intracellular loop (Val/Gln in the rLHR and Ile/His in the hLHR), four non-contiguous residues in the third intracellular loop (Arg/Gln/Thr/Pro in the rLHR and Lys/Arg/ Met/Thr in the hLHR), and one in the C-terminal tail (Leu in the rLHR and Phe in the hLHR), that are necessary and sufficient to impart the slow rate of internalization of the rLHR and the fast rate of internalization of the hLHR. The internalization of the rLHR and the hLHR display different sensitivities to the non-visual arrestins. Therefore, we also tested if the simultaneous exchange of these seven residues resulted in the exchange of this property. Since this was found to be the case, we propose that these seven residues identified here form a non-visual arrestin-binding site.Agonist binding to G protein-coupled receptors (GPCR) 1 is quickly followed by the internalization of the receptor or the agonist-receptor complex. This process is facilitated by the GPCR phosphorylation that follows agonist-induced activation, and it usually requires the formation of a binary complex between the agonist-activated GPCR and the non-visual arrestins. The non-visual arrestins bind clathrin with high affinity and serve as adaptor molecules that target agonist-activated phosphorylated GPCRs to clathrin-coated pits (1-4).The LHR is a member of the rhodopsin-like subfamily of GPCRs (5), and the agonist-LHR complex is internalized (6 -8) via clathrin-coated pits (9) following agonist-induced activation. Like other GPCRs, the agonist-induced LHR activation and phosphorylation, as well as the interaction of the LHR with a non-visual arrestin, can now be recognized as important steps in agonist-induced internalization of the LHR. Thus, the rate of internalization of the free LHR is slower than the rate of internalization of the agonist-receptor complex (8, 10) and the rate of internalization of a complex formed by the LHR and a weak partial agonist is slower than that of the complex formed by the LHR and a full agonist (11). Likewise, mutations of the LHR that impair signal transduction or induce constitutive activation impair or enhance agonist-induced internalization, respectively (10, 12). On the other hand, mutations of the LHR that do not affect agonist-induced activation, but impair agonist-induced rLHR phosphorylation, also impair agonist-induced internalization (13,14). Finally, the internalization of the agonist-LHR complex can be inhibited by co-transfection with dominant-negative mutants of the non-visual arrestins or by co-transfection with a dominant-negative mutant of dynamin (14, 15). Whereas most internalized GPCRs recycle qui...

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Co-migration and internalization of transferrin and its receptor on K562 cells.

Cited by 84 publications

References 21 publications

Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells.

Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells.

Ligation of the cell surface receptor, CD46, alters T cell polarity and response to antigen presentation

Seven Non-contiguous Intracellular Residues of the Lutropin/Choriogonadotropin Receptor Dictate the Rate of Agonist-induced Internalization and Its Sensitivity to Non-visual Arrestins

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