TTP specifically regulates the internalization of the transferrin receptor.
Different plasma membrane receptors are internalized through saturable/noncompetitive pathways, suggesting cargo-specific regulation. Here, we report that TTP (SH3BP4), a SH3-containing protein, specifically regulates the internalization of the transferrin receptor (TfR). TTP interacts with endocytic proteins, including clathrin, dynamin, and the TfR, and localizes selectively to TfR-containing coated-pits (CCP) and -vesicles (CCV). Overexpression of TTP specifically inhibits TfR internalization, and causes the formation of morphologically aberrant CCP, which are probably fission impaired. This effect is mediated by the SH3 of TTP, which can bind to dynamin, and it is rescued by overexpression of dynamin. Functional ablation of TTP causes a reduction in TfR internalization, and reduced cargo loading and size of TfR-CCV. Tyrosine phosphorylation of either TTP or dynamin prevents their interaction, pointing to a possible mechanism of exclusion of TTP from some CCP. Thus, TTP might represent one of the long sought for molecules that allow cargo-specific control of clathrin endocytosis.
Tosoni
Daniela
D
IFOM, Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
Puri
Claudia
C
Confalonieri
Stefano
S
Salcini
Anna Elisabetta
AE
De Camilli
Pietro
P
Tacchetti
Carlo
C
Di Fiore
Pier Paolo
PP
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002966:Clathrin / Q000235:genetics / Q000378:metabolism; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism; D018699:Coated Vesicles / Q000378:metabolism; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D015388:Organelles / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002966:Clathrin; D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; D011993:Recombinant Fusion Proteins; C404497:SH3BP4 protein, human; D034281:Dynamins