Regulation of endocytosis of activin type II receptors by a novel PDZ protein through Ral/Ral-binding protein 1-dependent pathway.
Using yeast two-hybrid screening, we have identified a mouse Postsynaptic density 95/Discs large/Zona occludens-1 (PDZ) protein that interacts with activin type II receptors (ActRIIs). We named the protein activin receptor-interacting protein 2 (ARIP2). ARIP2 was found to have one PDZ domain in the NH(2)-terminal region and interact specifically with ActRIIs among the receptors for the transforming growth factor beta family by the PDZ domain. Interestingly, overexpression of ARIP2 enhances endocytosis of ActRIIs and reduces activin-induced transcription in Chinese hamster ovary K1 cells. In addition, immunofluorescence co-localization studies indicated the direct involvement of ARIP2 in the intracellular translocation of ActRIIs by PDZ domain-mediated interaction. Moreover, we have identified that the COOH-terminal region of ARIP2 interacts with Ral-binding protein 1 (RalBP1). RalBP1 is a potential effector protein of small GTP-binding protein Ral and regulates endocytosis of epidermal growth factor and insulin receptors. The studies using deletion mutants of RalBP1 and constitutively GTP and GDP binding forms of Ral indicate that ARIP2 regulates endocytosis of ActRIIs through the Ral/RalBP1-dependent pathway, and the GDP-GTP exchange of Ral is critical for this regulation.
Matsuzaki
Takashi
T
Institute for Enzyme Research, The University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
Hanai
Sayuri
S
Kishi
Hisashi
H
Liu
ZhongHui
Z
Bao
YongLi
Y
Kikuchi
Akira
A
Tsuchida
Kunihiro
K
Sugino
Hiromu
H
D030301:Activin Receptors, Type II / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004705:Endocytosis / Q000502:physiology*; D005656:Fungal Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014158:Transcription, Genetic; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018076:DNA, Complementary; D005656:Fungal Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; C490620:Ralbp1 protein, mouse; C486752:SYNJ2BP protein, human; C457224:Synj2bp protein, mouse; D030301:Activin Receptors, Type II; D020725:ral GTP-Binding Proteins