Inhibitors of phosphoinositide 3-kinase cause defects in the postendocytic sorting of β2-adrenergic receptors

被引:5
作者
Awwad, Hibah O.
Iyer, Varsha
Rosenfeld, Jennifer L.
Millman, Ellen E.
Foster, Estrella
Moore, Robert H.
Knoll, Brian J.
机构
[1] Univ Houston, Dept Pharmacol & Pharmaceut Sci, Houston, TX 77204 USA
[2] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
关键词
PI; 3-kinase; beta 2-adrenergic receptors; rab7; lysosomes; endosomes;
D O I
10.1016/j.yexcr.2007.04.034
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Phosphatidylinositol 3-kinase inhibitors have been shown to affect endocytosis or subsequent intracellular sorting in various receptor systems. Agonist-activated beta(2)-adrenergic receptors undergo desensitization by mechanisms that include the phosphorylation, endocytosis and degradation of receptors. Following endocytosis, most internalized receptors are sorted to the cell surface, but some proportion is sorted to lysosomes for degradation. It is not known what governs the ratio of receptors that recycle versus receptors that undergo degradation. To determine if phosphatidylinositol 3-kinases regulate of beta(2)-adrenergic receptor trafficking, HEK293 cells stably expressing these receptors were treated with the phosphatidylinositol 3-kinase inhibitors LY294002 or wortmannin. We then studied agonist-induced receptor endocytosis and postendocytic sorting, including recycling and degradation of the internalized receptors. Both inhibitors amplified the internalization of receptors after exposure to the f-agonist isoproterenol, which was attributable to the sorting of a significant fraction of receptors to an intracellular compartment from which receptor recycling did not occur. The initial rate Of 1 beta 2(-) adrenergic receptor endocytosis and the default rate of receptor recycling were not significantly altered. During prolonged exposure to agonist, LY294002 slowed the degradation rate of beta 2-adrenergic receptors and caused the accumulation of receptors within rab7-positive vesicles. These results suggest that phosphatidylinositol 3-kinase inhibitors (1) cause a misrouting of beta 2-adrenergic receptors into vesicles that are neither able to efficiently recycle to the surface nor sort to lysosomes, and (2) delays the movement of receptors from late endosomes to lysosomes. (C) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:2586 / 2596
页数:11
相关论文
共 44 条
[21]  
Moore RH, 1999, J CELL SCI, V112, P329
[22]  
MOORE RH, 1995, J CELL SCI, V108, P2983
[23]  
Morrison KJ, 1996, MOL PHARMACOL, V50, P692
[24]   Rab7 regulates transport from early to late endocytic compartments in Xenopus oocytes [J].
Mukhopadhyay, A ;
Funato, K ;
Stahl, PD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (20) :13055-13059
[25]   Association of β-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization [J].
Oakley, RH ;
Laporte, SA ;
Holt, JA ;
Barak, LS ;
Caron, MG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (45) :32248-32257
[26]   PI3P signaling regulates receptor sorting but not transport in the endosomal pathway [J].
Petiot, A ;
Fauré, J ;
Stenmark, H ;
Gruenberg, J .
JOURNAL OF CELL BIOLOGY, 2003, 162 (06) :971-979
[27]   Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by β-adrenergic receptor kinase 1 -: A role in receptor sequestration [J].
Prasad, SVN ;
Barak, LS ;
Rapacciuolo, A ;
Caron, MG ;
Rockman, HA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (22) :18953-18959
[28]   Mutant Rab7 causes the accumulation of cathepsin D and cation-independent mannose 6-phosphate receptor in an early endocytic compartment [J].
Press, B ;
Feng, Y ;
Hoflack, B ;
Wandinger-Ness, A .
JOURNAL OF CELL BIOLOGY, 1998, 140 (05) :1075-1089
[29]  
Reaves BJ, 1996, J CELL SCI, V109, P749
[30]   PHOSPHATIDYLINOSITOL 3-KINASE ENCODED BY YEAST VPS34 GENE ESSENTIAL FOR PROTEIN SORTING [J].
SCHU, PV ;
TAKEGAWA, K ;
FRY, MJ ;
STACK, JH ;
WATERFIELD, MD ;
EMR, SD .
SCIENCE, 1993, 260 (5104) :88-91