PMID- 35793126
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20230720
IS  - 1939-4586 (Electronic)
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 33
IP  - 10
DP  - 2022 Sep 1
TI  - Docking of Syk to FcepsilonRI is enhanced by Lyn but limited in duration by SHIP1.
PG  - ar89
LID - 10.1091/mbc.E21-12-0603 [doi]
LID - ar89
AB  - The high-affinity immunoglobulin E (IgE) receptor, FcepsilonRI, is the primary immune 
      receptor found on mast cells and basophils. Signal initiation is classically 
      attributed to phosphorylation of FcepsilonRI beta- and gamma-subunits by the Src family kinase 
      (SFK) Lyn, followed by the recruitment and activation of the tyrosine kinase Syk. 
      FcepsilonRI signaling is tuned by the balance between Syk-driven positive signaling and 
      the engagement of inhibitory molecules, including SHIP1. Here, we investigate the 
      mechanistic contributions of Lyn, Syk, and SHIP1 to the formation of the FcepsilonRI 
      signalosome. Using Lyn-deficient RBL-2H3 mast cells, we found that another SFK 
      can weakly monophosphorylate the gamma-subunit, yet Syk still binds the incompletely 
      phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs). Once 
      recruited, Syk further enhances gamma-phosphorylation to propagate signaling. In 
      contrast, the loss of SHIP1 recruitment indicates that Lyn is required for 
      phosphorylation of the beta-subunit. We demonstrate two noncanonical Syk binding 
      modes, trans gamma-bridging and direct beta-binding, that can support signaling when 
      SHIP1 is absent. Using single particle tracking, we reveal a novel role of SHIP1 
      in regulating Syk activity, where the presence of SHIP1 in the signaling complex 
      acts to increase the Syk:receptor off-rate. These data suggest that the 
      composition and dynamics of the signalosome modulate immunoreceptor signaling 
      activities.
FAU - Kanagy, William K
AU  - Kanagy WK
AD  - Department of Pathology, University of New Mexico, Albuquerque, NM 87131.
FAU - Cleyrat, Cedric
AU  - Cleyrat C
AD  - Department of Pathology, University of New Mexico, Albuquerque, NM 87131.
AD  - Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131.
FAU - Fazel, Mohamadreza
AU  - Fazel M
AD  - Department of Physics, University of New Mexico, Albuquerque, NM 87131.
FAU - Lucero, Shayna R
AU  - Lucero SR
AD  - Department of Pathology, University of New Mexico, Albuquerque, NM 87131.
FAU - Bruchez, Marcel P
AU  - Bruchez MP
AD  - Department of Biological Sciences and Department of Chemistry, Carnegie Mellon 
      University, Pittsburgh, PA 15213.
FAU - Lidke, Keith A
AU  - Lidke KA
AD  - Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131.
AD  - Department of Physics, University of New Mexico, Albuquerque, NM 87131.
FAU - Wilson, Bridget S
AU  - Wilson BS
AD  - Department of Pathology, University of New Mexico, Albuquerque, NM 87131.
AD  - Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131.
FAU - Lidke, Diane S
AU  - Lidke DS
AD  - Department of Pathology, University of New Mexico, Albuquerque, NM 87131.
AD  - Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131.
LA  - eng
GR  - R01 GM114075/GM/NIGMS NIH HHS/United States
GR  - R35 GM126934/GM/NIGMS NIH HHS/United States
GR  - P50 GM085273/GM/NIGMS NIH HHS/United States
GR  - P30 CA118100/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220706
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Receptors, IgE)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Syk Kinase)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - *Intracellular Signaling Peptides and Proteins/metabolism
MH  - Mast Cells/metabolism
MH  - Phosphorylation
MH  - Protein-Tyrosine Kinases/metabolism
MH  - *Receptors, IgE/metabolism
MH  - Syk Kinase/metabolism
MH  - src-Family Kinases/metabolism
PMC - PMC9582627
EDAT- 2022/07/07 06:00
MHDA- 2022/08/23 06:00
PMCR- 2022/11/02
CRDT- 2022/07/06 11:52
PHST- 2022/07/07 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/07/06 11:52 [entrez]
PHST- 2022/11/02 00:00 [pmc-release]
AID - E21-12-0603 [pii]
AID - 10.1091/mbc.E21-12-0603 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2022 Sep 1;33(10):ar89. doi: 10.1091/mbc.E21-12-0603. Epub 2022 
      Jul 6.