PMID- 34572081
OWN - NLM
STAT- MEDLINE
DCOM- 20211116
LR  - 20230921
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 9
DP  - 2021 Sep 15
TI  - L-Plastin Phosphorylation: Possible Regulation by a TNFR1 Signaling Cascade in 
      Osteoclasts.
LID - 10.3390/cells10092432 [doi]
LID - 2432
AB  - Tumor necrosis factor-alpha (TNF-alpha) signaling regulates phosphorylation of 
      L-plastin, which is involved in forming the nascent sealing zone, a precursor 
      zone for the matured sealing ring. This study aimed to illustrate the molecular 
      mechanisms of L-plastin phosphorylation and the subsequent formation of the 
      nascent sealing zone in osteoclasts treated with TNF-alpha. Here, we report that 
      anti-TNF-receptor 1, inhibitors of signaling proteins (Src, PI3-K, Rho, and 
      Rho-kinase), and siRNA of TRAF-6 attenuated the phosphorylation of LPL and 
      filamentous actin content significantly in the presence of TNF-alpha. An inhibitor of 
      integrin alphavbeta3, PKC, or PKA did not inhibit TNF-alpha-induced L-plastin 
      phosphorylation. Inhibitors of Src and PI3-K and not Rho or Rho-kinase reduced 
      tyrosine phosphorylation of TRAF-6, suggesting that Src and PI3-K regulate TRAF-6 
      phosphorylation, and Rho and Rho-kinase are downstream of TRAF-6 regulation. 
      Osteoclasts expressing constitutively active or kinase-defective Src proteins 
      were used to determine the role of Src on L-plastin phosphorylation; similarly, 
      the effect of Rho was confirmed by transducing TAT-fused constitutively active 
      (V14) or dominant-negative (N19) Rho proteins into osteoclasts. Pull-down 
      analysis with glutathione S-transferase-fused SH2 and SH3 domains of Src and 
      PI3-K demonstrated coprecipitation of L-plastin and TRAF-6 with the SH3 and SH2 
      domains of the PI3-K and Src proteins. However, the actual order of the 
      interaction of proteins requires further elucidation; a comprehensive screening 
      should corroborate the initial findings of protein interactions via the SH2/SH3 
      domains. Ultimately, inhibition of the interaction of proteins with SH2/SH3 could 
      reduce L-plastin phosphorylation and affect NSZ formation and bone resorption in 
      conditions that display osteoclast activation and bone loss.
FAU - Chellaiah, Meenakshi A
AU  - Chellaiah MA
AD  - Department of Oncology and Diagnostic Sciences, School of Dentistry, University 
      of Maryland, Baltimore, MD 21201, USA.
LA  - eng
GR  - R01 AR066044/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210915
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Actins)
RN  - 0 (LCP1 protein, human)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Microfilament Proteins)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (TNF Receptor-Associated Factor 6)
RN  - 0 (Tumor Necrosis Factor Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (plastin)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Bone Resorption/metabolism
MH  - Membrane Glycoproteins/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microfilament Proteins/*metabolism
MH  - Osteoclasts/cytology/drug effects/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Interaction Domains and Motifs/drug effects
MH  - Receptors, Tumor Necrosis Factor, Type I/drug effects/*metabolism
MH  - Signal Transduction/drug effects
MH  - TNF Receptor-Associated Factor 6/metabolism
MH  - Tumor Necrosis Factor Inhibitors/pharmacology
MH  - Tumor Necrosis Factor-alpha/metabolism/pharmacology
MH  - src Homology Domains/drug effects
MH  - src-Family Kinases/metabolism
PMC - PMC8464874
OTO - NOTNLM
OT  - L-plastin
OT  - SH2/SH3 domains
OT  - Src
OT  - TRAF-6
OT  - nascent sealing zone
OT  - phosphorylation
COIS- The author declares no conflict of interest.
EDAT- 2021/09/29 06:00
MHDA- 2021/11/17 06:00
PMCR- 2021/09/15
CRDT- 2021/09/28 01:04
PHST- 2021/07/15 00:00 [received]
PHST- 2021/08/25 00:00 [revised]
PHST- 2021/09/09 00:00 [accepted]
PHST- 2021/09/28 01:04 [entrez]
PHST- 2021/09/29 06:00 [pubmed]
PHST- 2021/11/17 06:00 [medline]
PHST- 2021/09/15 00:00 [pmc-release]
AID - cells10092432 [pii]
AID - cells-10-02432 [pii]
AID - 10.3390/cells10092432 [doi]
PST - epublish
SO  - Cells. 2021 Sep 15;10(9):2432. doi: 10.3390/cells10092432.