LAPTM4B is a PtdIns(4,5)P2 effector that regulates EGFR signaling, lysosomal sorting, and degradation
Identifieur interne : 000F47 ( Main/Exploration ); précédent : 000F46; suivant : 000F48LAPTM4B is a PtdIns(4,5)P2 effector that regulates EGFR signaling, lysosomal sorting, and degradation
Auteurs : Xiaojun Tan [États-Unis] ; Yue Sun [États-Unis] ; Narendra Thapa [États-Unis] ; Yihan Liao [États-Unis] ; Andrew C. Hedman [États-Unis] ; Richard A. Anderson [États-Unis]Source :
- The EMBO Journal [ 0261-4189 ] ; 2015-02-12.
Abstract
Lysosomal degradation is essential for the termination of EGF‐stimulated EGF receptor (EGFR) signaling. This requires EGFR sorting to the intraluminal vesicles (ILVs) of multi‐vesicular endosomes (MVEs). Cytosolic proteins including the ESCRT machineries are key regulators of EGFR intraluminal sorting, but roles for endosomal transmembrane proteins in receptor sorting are poorly defined. Here, we show that LAPTM4B, an endosomal transmembrane oncoprotein, inhibits EGF‐induced EGFR intraluminal sorting and lysosomal degradation, leading to enhanced and prolonged EGFR signaling. LAPTM4B blocks EGFR sorting by promoting ubiquitination of Hrs (an ESCRT‐0 subunit), which inhibits the Hrs association with ubiquitinated EGFR. This is counteracted by the endosomal PIP kinase, PIPKIγi5, which directly binds LAPTM4B and neutralizes the inhibitory function of LAPTM4B in EGFR sorting by generating PtdIns(4,5)P2 and recruiting SNX5. PtdIns(4,5)P2 and SNX5 function together to protect Hrs from ubiquitination, thereby promoting EGFR intraluminal sorting. These results reveal an essential layer of EGFR trafficking regulated by LAPTM4B, PtdIns(4,5)P2 signaling, and the ESCRT complex and define a mechanism by which the oncoprotein LAPTM4B can transform cells and promote tumor progression.
The oncogene LAPTM4B prolongs EGFR signalling. LAPTM4B promotes ubiquitination of ESCRT component Hrs, preventing endosomal EGFR sorting, which is counteracted by phosphoinositide PtdIns(4,5)P2. LAPTM4B inhibits EGF‐stimulated EGFR‐intraluminal sorting and degradation and enhances EGFR signaling LAPTM4B promotes Hrs ubiquitination by the E3 ubiquitin ligase Nedd4 LAPTM4B interacts with PIPKIγi5, an enzyme generating PtdIns(4,5)P2 at endosomes LAPTM4B is a PtdIns(4,5)P2 effector, and PtdIns(4,5)P2 binding alleviates the inhibitory effect of LAPTM4B on EGFR degradation
The oncogene LAPTM4B prolongs EGFR signalling. LAPTM4B promotes ubiquitination of ESCRT component Hrs, preventing endosomal EGFR sorting, which is counteracted by phosphoinositide PtdIns(4,5)P2.
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DOI: 10.15252/embj.201489425
Affiliations:
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This requires EGFR sorting to the intraluminal vesicles (ILVs) of multi‐vesicular endosomes (MVEs). Cytosolic proteins including the ESCRT machineries are key regulators of EGFR intraluminal sorting, but roles for endosomal transmembrane proteins in receptor sorting are poorly defined. Here, we show that LAPTM4B, an endosomal transmembrane oncoprotein, inhibits EGF‐induced EGFR intraluminal sorting and lysosomal degradation, leading to enhanced and prolonged EGFR signaling. LAPTM4B blocks EGFR sorting by promoting ubiquitination of Hrs (an ESCRT‐0 subunit), which inhibits the Hrs association with ubiquitinated EGFR. This is counteracted by the endosomal PIP kinase, PIPKIγi5, which directly binds LAPTM4B and neutralizes the inhibitory function of LAPTM4B in EGFR sorting by generating PtdIns(4,5)P2 and recruiting SNX5. PtdIns(4,5)P2 and SNX5 function together to protect Hrs from ubiquitination, thereby promoting EGFR intraluminal sorting. These results reveal an essential layer of EGFR trafficking regulated by LAPTM4B, PtdIns(4,5)P2 signaling, and the ESCRT complex and define a mechanism by which the oncoprotein LAPTM4B can transform cells and promote tumor progression.</div><div type="abstract">The oncogene LAPTM4B prolongs EGFR signalling. LAPTM4B promotes ubiquitination of ESCRT component Hrs, preventing endosomal EGFR sorting, which is counteracted by phosphoinositide PtdIns(4,5)P2. LAPTM4B inhibits EGF‐stimulated EGFR‐intraluminal sorting and degradation and enhances EGFR signaling LAPTM4B promotes Hrs ubiquitination by the E3 ubiquitin ligase Nedd4 LAPTM4B interacts with PIPKIγi5, an enzyme generating PtdIns(4,5)P2 at endosomes LAPTM4B is a PtdIns(4,5)P2 effector, and PtdIns(4,5)P2 binding alleviates the inhibitory effect of LAPTM4B on EGFR degradation</div><div type="abstract">The oncogene LAPTM4B prolongs EGFR signalling. LAPTM4B promotes ubiquitination of ESCRT component Hrs, preventing endosomal EGFR sorting, which is counteracted by phosphoinositide PtdIns(4,5)P2.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Tan, Xiaojun" sort="Tan, Xiaojun" uniqKey="Tan X" first="Xiaojun" last="Tan">Xiaojun Tan</name></noRegion><name sortKey="Anderson, Richard A" sort="Anderson, Richard A" uniqKey="Anderson R" first="Richard A" last="Anderson">Richard A. Anderson</name><name sortKey="Anderson, Richard A" sort="Anderson, Richard A" uniqKey="Anderson R" first="Richard A" last="Anderson">Richard A. Anderson</name><name sortKey="Hedman, Andrew C" sort="Hedman, Andrew C" uniqKey="Hedman A" first="Andrew C" last="Hedman">Andrew C. Hedman</name><name sortKey="Liao, Yihan" sort="Liao, Yihan" uniqKey="Liao Y" first="Yihan" last="Liao">Yihan Liao</name><name sortKey="Sun, Yue" sort="Sun, Yue" uniqKey="Sun Y" first="Yue" last="Sun">Yue Sun</name><name sortKey="Thapa, Narendra" sort="Thapa, Narendra" uniqKey="Thapa N" first="Narendra" last="Thapa">Narendra Thapa</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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