PMID- 20522958
OWN - NLM
STAT- MEDLINE
DCOM- 20110110
LR  - 20191210
IS  - 1347-5215 (Electronic)
IS  - 0918-6158 (Linking)
VI  - 33
IP  - 6
DP  - 2010
TI  - Nedd4-interacting protein 2, a short half-life membrane protein degraded in 
      lysosomes, negatively controls down-regulation of connexin43.
PG  - 951-7
AB  - Nedd4-interacting protein 2 (NDFIP2) has three transmembrane domains and 
      interacts with multiple Nedd4 family ubiquitin ligases through 
      polyprolinetyrosine (PY) motifs located in its N-terminal cytoplasmic domain. It 
      has been postulated that NDFIP2 acts as an adaptor for the ubiquitylation of 
      substrates with Nedd4 ubiquitin ligase. However, whether NDFIP2 promotes or 
      inhibits the ubiquitylation of Nedd4 substrates is still under debate. We show 
      here that although NDFIP2 is detected in the Golgi/trans-Golgi network (TGN) 
      area, it is rapidly delivered to and degraded in lysosomes with its half-life ca. 
      1.5 h. Intriguingly, knockdown (KD) of NDFIP2 with small interfering RNA (siRNA) 
      impaired both the formation and function of gap junctions. Indeed, KD of NDFIP2 
      destabilized the gap junction protein connexin43 that contains PY motif. In 
      support of this, overexpression of NDFIP2 stabilized connexin43 and enhanced the 
      formation of gap junctions. Furthermore, the PY motifs of NDFIP2, which are 
      required for its interaction with Nedd4, Atrophin-1 interacting protein (AIP) 4 
      (AIP4)/Itch, and AIP2/WWP2, were necessary for the targeting of NDFIP2 to 
      lysosomes and/or the stability of connexin43 and gap junctions. Collectively 
      these findings suggest that NDFIP2 may inhibit the Nedd4-dependent ubiquitylation 
      of membrane proteins containing PY motifs, such as connexin43, in a competitive 
      manner.
FAU - Ohzono, Chiho
AU  - Ohzono C
AD  - Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical 
      Sciences, Kyushu University, Fukuoka 812-8582, Japan.
FAU - Etoh, Sachise
AU  - Etoh S
FAU - Matsumoto, Masaki
AU  - Matsumoto M
FAU - Nakayama, Keiichi I
AU  - Nakayama KI
FAU - Hirota, Yuko
AU  - Hirota Y
FAU - Tanaka, Yoshitaka
AU  - Tanaka Y
FAU - Fujita, Hideaki
AU  - Fujita H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 0 (Carrier Proteins)
RN  - 0 (Connexin 43)
RN  - 0 (Endosomal Sorting Complexes Required for Transport)
RN  - 0 (N4BP2 protein, human)
RN  - 0 (Peptides)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.3.2.26 (NEDD4L protein, rat)
RN  - EC 2.3.2.26 (Nedd4 Ubiquitin Protein Ligases)
RN  - EC 2.3.2.26 (Nedd4 protein, human)
RN  - EC 2.3.2.26 (Nedd4 protein, rat)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 6.5.1.- (DNA Repair Enzymes)
SB  - IM
MH  - Animals
MH  - COS Cells
MH  - Carrier Proteins/*metabolism
MH  - Chlorocebus aethiops
MH  - Connexin 43/*metabolism
MH  - DNA Repair Enzymes
MH  - Down-Regulation/drug effects
MH  - Endosomal Sorting Complexes Required for Transport/*metabolism
MH  - Gap Junctions/*physiology
MH  - Golgi Apparatus/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Lysosomes/*metabolism
MH  - Nedd4 Ubiquitin Protein Ligases
MH  - Peptides/metabolism
MH  - RNA, Small Interfering
MH  - Rats
MH  - Ubiquitin-Protein Ligases/*metabolism
MH  - *Ubiquitination
MH  - trans-Golgi Network/metabolism
EDAT- 2010/06/05 06:00
MHDA- 2011/01/11 06:00
CRDT- 2010/06/05 06:00
PHST- 2010/06/05 06:00 [entrez]
PHST- 2010/06/05 06:00 [pubmed]
PHST- 2011/01/11 06:00 [medline]
AID - JST.JSTAGE/bpb/33.951 [pii]
AID - 10.1248/bpb.33.951 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2010;33(6):951-7. doi: 10.1248/bpb.33.951.