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Cbl与表皮生长因子受体(EGFR)的酪氨酸1045位点直接相互作用,是将EGFR分选至溶酶体进行降解所必需的。

Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation.

作者信息

Grøvdal Lene Melsaether, Stang Espen, Sorkin Alexander, Madshus Inger Helene

机构信息

Institute of Pathology, University of Oslo, Rikshospitalet, N-0027 Oslo, Norway.

出版信息

Exp Cell Res. 2004 Nov 1;300(2):388-95. doi: 10.1016/j.yexcr.2004.07.003.

Abstract

Mutation of the binding site for Cbl (Tyr1045) in the EGF receptor (EGFR) results in impaired ubiquitination but does not affect EGFR internalization. However, the Y1045F mutation resulted in strongly decreased degradation of the EGFR, as well as efficient recycling of EGFR to the plasma membrane. Significantly, more wild-type EGFR than Y1045F EGFR was found localizing to multivesicular late endosomes. Ubiquitination of the EGFR was in HeLa cells inhibited both upon overexpressing the N-terminal part of Cbl and upon overexpressing a double mutant Grb2 incapable of interacting with Cbl and thereby being incapable of indirectly recruiting Cbl to the EGFR. Collectively, these data suggest that the ubiquitination resulting from direct binding of Cbl to pTyr1045 of the EGFR is critical for lysosomal sorting of the EGFR in contrast to ubiquitination resulting from Grb2-mediated binding of Cbl to the EGFR.

摘要

表皮生长因子受体(EGFR)中Cbl结合位点(Tyr1045)的突变导致泛素化受损,但不影响EGFR的内化。然而,Y1045F突变导致EGFR的降解显著减少,以及EGFR有效地循环回到质膜。值得注意的是,发现定位在多囊泡晚期内体上的野生型EGFR比Y1045F EGFR更多。在HeLa细胞中,过表达Cbl的N端部分以及过表达不能与Cbl相互作用从而不能间接将Cbl招募到EGFR的双突变体Grb2时,EGFR的泛素化均受到抑制。总体而言,这些数据表明,与Grb2介导的Cbl与EGFR结合所导致的泛素化相比,Cbl直接与EGFR的pTyr1045结合所导致的泛素化对于EGFR的溶酶体分选至关重要。

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