LAPTM4B is a PtdIns(4,5)P2 effector that regulates EGFR signaling, lysosomal sorting, and degradation.

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.

• Authors: Xiaojun Tan, Yue Sun, Narendra Thapa, Yihan Liao, Andrew C Hedman, Richard A Anderson
• Journal: The EMBO journal (EMBO J) Vol. 34 Issue 4 Pg. 475-90 (Feb 12 2015) ISSN: 1460-2075 [Electronic] England
• PMID: 25588945 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors.

Chemical References

• LAPTM4B protein, human
• Membrane Proteins
• Oncogene Proteins
• Phosphatidylinositols
• SNX5 protein, human
• Sorting Nexins
• ErbB Receptors

Topics

• Cell Line
• ErbB Receptors (metabolism)
• Humans
• Lysosomes (metabolism)
• Membrane Proteins (genetics, metabolism)
• Microscopy, Fluorescence
• Models, Biological
• Oncogene Proteins (genetics, metabolism)
• Phosphatidylinositols (metabolism)
• Protein Binding
• Signal Transduction (physiology)
• Sorting Nexins (metabolism)