title: 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.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Tan
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Thapa
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hedman
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA raanders@wisc.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology; D058305:Sorting Nexins / Q000378:metabolism
chemical_list: C477083:LAPTM4B protein, human; D008565:Membrane Proteins; D015513:Oncogene Proteins; D010716:Phosphatidylinositols; C402667:SNX5 protein, human; D058305:Sorting Nexins; D066246:ErbB Receptors
keywords: EGFR; LAPTM4B; PIPKIγi5; PtdIns(4,5)P2