PMID- 31913757
OWN - NLM
STAT- MEDLINE
DCOM- 20210122
LR  - 20210122
IS  - 1939-4586 (Electronic)
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 31
IP  - 5
DP  - 2020 Mar 1
TI  - TGFbeta receptor endocytosis and Smad signaling require synaptojanin1, PI3K-C2alpha-, 
      and INPP4B-mediated phosphoinositide conversions.
PG  - 360-372
LID - 10.1091/mbc.E19-11-0662 [doi]
AB  - Phosphoinositide conversion regulates a diverse array of dynamic membrane events 
      including endocytosis. However, it is not well understood which enzymes are 
      involved in phosphoinositide conversions for receptor endocytosis. We found by 
      small interfering RNA (siRNA)-mediated knockdown (KD) that class II PI3K 
      alpha-isoform (PI3K-C2alpha), the 5'-phosphatase synaptojanin1 (Synj1), and the 
      4'-phosphatase INPP4B, but not PI3K-C2beta, Synj2, or INPP4A, were required for 
      TGFbeta-induced endocytosis of TGFbeta receptor. TGFbeta induced rapid decreases in 
      PI(4,5)P(2) at the plasma membrane (PM) with increases in PI(4)P, followed by 
      increases in PI(3,4)P(2), in a TGFbeta receptor kinase ALK5-dependent manner. TGFbeta 
      induced the recruitment of both synaptojanin1 and PI3K-C2alpha to the PM with their 
      substantial colocalization. Knockdown of synaptojanin1 abolished TGFbeta-induced 
      PI(4,5)P(2) decreases and PI(4)P increases. Interestingly, PI3K-C2alpha KD abolished 
      not only TGFbeta-induced PI(3,4)P(2) increases but also TGFbeta-induced synaptojanin1 
      recruitment to the PM, PI(4,5)P(2) decreases, and PI(4)P increases. Finally, the 
      phosphoinositide conversions were necessary for TGFbeta-induced activation of Smad2 
      and Smad3. These observations demonstrate that the sequential phosphoinositide 
      conversions mediated by Synj1, PI3K-C2alpha, and INPP4B are essential for TGFbeta 
      receptor endocytosis and its signaling.
FAU - Aki, Sho
AU  - Aki S
AD  - Department of Physiology, Kanazawa University School of Medicine, Kanazawa, 
      Ishikawa 920-8640, Japan.
FAU - Yoshioka, Kazuaki
AU  - Yoshioka K
AD  - Department of Physiology, Kanazawa University School of Medicine, Kanazawa, 
      Ishikawa 920-8640, Japan.
FAU - Takuwa, Noriko
AU  - Takuwa N
AD  - Department of Health Science, Ishikawa Prefectural University, Kahoku, Ishikawa 
      929-1210, Japan.
FAU - Takuwa, Yoh
AU  - Takuwa Y
AD  - Department of Physiology, Kanazawa University School of Medicine, Kanazawa, 
      Ishikawa 920-8640, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200108
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Phosphatidylinositols)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Smad Proteins)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 2.7.11.30 (ACVRL1 protein, human)
RN  - EC 2.7.11.30 (Activin Receptors, Type II)
RN  - EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type I)
RN  - EC 2.7.11.30 (TGFBR1 protein, human)
RN  - EC 3.1.3.- (synaptojanin)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.1.3.66 (phosphatidylinositol-3,4-bisphosphate 4-phosphatase)
SB  - IM
MH  - Activin Receptors, Type II/metabolism
MH  - Cell Membrane/metabolism
MH  - Cell Nucleus/metabolism
MH  - *Endocytosis
MH  - Human Umbilical Vein Endothelial Cells/metabolism
MH  - Humans
MH  - Nerve Tissue Proteins/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphatidylinositols/*metabolism
MH  - Phosphoric Monoester Hydrolases/*metabolism
MH  - Phosphorylation
MH  - Receptor, Transforming Growth Factor-beta Type I/metabolism
MH  - Receptors, Transforming Growth Factor beta/*metabolism
MH  - *Signal Transduction
MH  - Smad Proteins/*metabolism
MH  - Transforming Growth Factor beta/metabolism
PMC - PMC7183790
EDAT- 2020/01/09 06:00
MHDA- 2021/01/23 06:00
PMCR- 2020/05/16
CRDT- 2020/01/09 06:00
PHST- 2020/01/09 06:00 [pubmed]
PHST- 2021/01/23 06:00 [medline]
PHST- 2020/01/09 06:00 [entrez]
PHST- 2020/05/16 00:00 [pmc-release]
AID - E19-11-0662 [pii]
AID - 10.1091/mbc.E19-11-0662 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2020 Mar 1;31(5):360-372. doi: 10.1091/mbc.E19-11-0662. Epub 2020 
      Jan 8.