PMID- 30116247
OWN - NLM
STAT- MEDLINE
DCOM- 20191007
LR  - 20191210
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 9
DP  - 2018
TI  - Positive and Negative Regulatory Roles of C-Terminal Src Kinase (CSK) in 
      FcepsilonRI-Mediated Mast Cell Activation, Independent of the Transmembrane Adaptor 
      PAG/CSK-Binding Protein.
PG  - 1771
LID - 10.3389/fimmu.2018.01771 [doi]
LID - 1771
AB  - C-terminal Src kinase (CSK) is a major negative regulator of Src family tyrosine 
      kinases (SFKs) that play critical roles in immunoreceptor signaling. CSK is 
      brought in contiguity to the plasma membrane-bound SFKs via binding to 
      transmembrane adaptor PAG, also known as CSK-binding protein. The recent finding 
      that PAG can function as a positive regulator of the high-affinity IgE receptor 
      (FcepsilonRI)-mediated mast cell signaling suggested that PAG and CSK have some 
      non-overlapping regulatory functions in mast cell activation. To determine the 
      regulatory roles of CSK in FcepsilonRI signaling, we derived bone marrow-derived mast 
      cells (BMMCs) with reduced or enhanced expression of CSK from wild-type (WT) or 
      PAG knockout (KO) mice and analyzed their FcepsilonRI-mediated activation events. We 
      found that in contrast to PAG-KO cells, antigen-activated BMMCs with CSK 
      knockdown (KD) exhibited significantly higher degranulation, calcium response, 
      and tyrosine phosphorylation of FcepsilonRI, SYK, and phospholipase C. Interestingly, 
      FcepsilonRI-mediated events in BMMCs with PAG-KO were restored upon CSK silencing. 
      BMMCs with CSK-KD/PAG-KO resembled BMMCs with CSK-KD alone. Unexpectedly, cells 
      with CSK-KD showed reduced kinase activity of LYN and decreased phosphorylation 
      of transcription factor STAT5. This was accompanied by impaired production of 
      proinflammatory cytokines and chemokines in antigen-activated cells. In line with 
      this, BMMCs with CSK-KD exhibited enhanced phosphorylation of protein phosphatase 
      SHP-1, which provides a negative feedback loop for regulating phosphorylation of 
      STAT5 and LYN kinase activity. Furthermore, we found that in WT BMMCs SHP-1 forms 
      complexes containing LYN, CSK, and STAT5. Altogether, our data demonstrate that 
      in FcepsilonRI-activated mast cells CSK is a negative regulator of degranulation and 
      chemotaxis, but a positive regulator of adhesion to fibronectin and production of 
      proinflammatory cytokines. Some of these pathways are not dependent on the 
      presence of PAG.
FAU - Potuckova, Lucie
AU  - Potuckova L
AD  - Department of Signal Transduction, Institute of Molecular Genetics of the Czech 
      Academy of Sciences, Prague, Czechia.
FAU - Draberova, Lubica
AU  - Draberova L
AD  - Department of Signal Transduction, Institute of Molecular Genetics of the Czech 
      Academy of Sciences, Prague, Czechia.
FAU - Halova, Ivana
AU  - Halova I
AD  - Department of Signal Transduction, Institute of Molecular Genetics of the Czech 
      Academy of Sciences, Prague, Czechia.
FAU - Paulenda, Tomas
AU  - Paulenda T
AD  - Department of Signal Transduction, Institute of Molecular Genetics of the Czech 
      Academy of Sciences, Prague, Czechia.
FAU - Draber, Petr
AU  - Draber P
AD  - Department of Signal Transduction, Institute of Molecular Genetics of the Czech 
      Academy of Sciences, Prague, Czechia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180802
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Cytokines)
RN  - 0 (Fibronectins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Pag protein, mouse)
RN  - 0 (Pag1 protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (Receptors, IgE)
RN  - 0 (STAT5 Transcription Factor)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.2 (CSK Tyrosine-Protein Kinase)
RN  - EC 2.7.10.2 (lyn protein-tyrosine kinase)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.10.23 (CSK protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
RN  - EC 3.1.3.48 (Ptpn6 protein, mouse)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Bone Marrow Cells/physiology
MH  - CSK Tyrosine-Protein Kinase
MH  - Calcium/metabolism
MH  - Cell Degranulation
MH  - Cytokines/metabolism
MH  - Fibronectins/metabolism
MH  - Genetic Vectors
MH  - HEK293 Cells
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins
MH  - Mast Cells/*physiology
MH  - Membrane Proteins/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism
MH  - Receptors, IgE/*metabolism
MH  - STAT5 Transcription Factor/metabolism
MH  - Signal Transduction/immunology
MH  - Tyrosine/metabolism
MH  - src-Family Kinases/metabolism/*physiology
PMC - PMC6082945
OTO - NOTNLM
OT  - C-terminal Src kinase
OT  - LYN
OT  - SHP-1
OT  - STAT5
OT  - cytokines
OT  - degranulation
OT  - mast cell
OT  - phosphoprotein associated with glycosphingolipid-enriched microdomains
EDAT- 2018/08/18 06:00
MHDA- 2019/10/08 06:00
PMCR- 2018/01/01
CRDT- 2018/08/18 06:00
PHST- 2018/03/18 00:00 [received]
PHST- 2018/07/17 00:00 [accepted]
PHST- 2018/08/18 06:00 [entrez]
PHST- 2018/08/18 06:00 [pubmed]
PHST- 2019/10/08 06:00 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2018.01771 [doi]
PST - epublish
SO  - Front Immunol. 2018 Aug 2;9:1771. doi: 10.3389/fimmu.2018.01771. eCollection 
      2018.