Dysregulation of Ack1 inhibits down-regulation of the EGF receptor |
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Authors: | Grøvdal Lene Melsaether Johannessen Lene E Rødland Marianne Skeie Madshus Inger Helene Stang Espen |
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Institution: | University of Oslo, Institute of Pathology, Rikshospitalet HF, Oslo, Norway. |
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Abstract: | The protein tyrosine kinase Ack1 has been linked to cancer when over-expressed. Ack1 has also been suggested to function in clathrin-mediated endocytosis and in down-regulation of the epidermal growth factor (EGF) receptor (EGFR). We have studied the intracellular localization of over-expressed Ack1 and found that Ack1 co-localizes with the EGFR upon EGF-induced endocytosis in cells with moderate over-expression of Ack. This co-localization is mainly observed in early endosomes. Furthermore, we found that over-expression of Ack1 retained the EGFR at the limiting membrane of early endosomes, inhibiting sorting to inner vesicles of multivesicular bodies. Down-regulation of Ack1 in HeLa cells resulted in reduced rate of (125)I-EGF internalization, whereas internalization of (125)I-transferrin was not affected. In cells where Ack1 had been knocked down by siRNA, recycling of internalized (125)I-EGF was increased, while degradation of (125)I-EGF was inhibited. Together, these data suggest that Ack1 is involved in an early step of EGFR desensitization. |
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Keywords: | Ack activated Cdc42-associated kinase AP-2 adaptor protein complex 2 EGF epidermal growth factor EGFR EGF receptor MVB multivesicular body SNX9 sorting nexin 9 Tf Transferrin TfR transferrin receptor |
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