Govers R, van Kerkhof P, Schwartz A L, Strous G J
Department of Cell Biology, Faculty of Medicine and Institute of Biomembranes, Utrecht University, 3584 CX Utrecht, The Netherlands.
J Biol Chem. 1998 Jun 26;273(26):16426-33. doi: 10.1074/jbc.273.26.16426.
The growth hormone receptor (GHR) is a member of the cytokine receptor family. Its function is to mediate cellular responses upon binding of growth hormone. Ligand binding induces dimerization and activation of the GHR. One mechanism by which the GHR is rapidly inactivated involves the ubiquitin conjugation system, a system implicated in the degradation of cytosolic and nuclear proteins. We have shown previously that the ubiquitin-conjugating system mediates internalization of the GHR. Here, we present evidence that in addition to the ubiquitin-dependent endocytosis signal, the cytosolic tail of the GHR contains a di-leucine motif. Upon truncation of the GHR at amino acid residue 349, this di-leucine motif is activated and mediates ubiquitin-independent internalization of the receptor. Di-leucine-mediated GHR internalization requires functional clathrin-coated pits and results in GHR transport to the lysosome. Although the full-length GHR internalizes independent of the di-leucine motif, this motif may function in internalization of GHR isoforms.
生长激素受体（GHR）是细胞因子受体家族的成员。其功能是在生长激素结合后介导细胞反应。配体结合诱导GHR二聚化并激活。GHR快速失活的一种机制涉及泛素缀合系统，该系统与胞质和核蛋白的降解有关。我们之前已经表明泛素缀合系统介导GHR的内化。在此，我们提供证据表明，除了泛素依赖性内吞信号外，GHR的胞质尾含有一个双亮氨酸基序。在GHR在氨基酸残基349处截短后，这个双亮氨酸基序被激活并介导受体的泛素非依赖性内化。双亮氨酸介导的GHR内化需要功能性网格蛋白包被小窝，并导致GHR转运至溶酶体。虽然全长GHR的内化不依赖于双亮氨酸基序，但该基序可能在GHR异构体的内化中起作用。
