PMID- 18039660
OWN - NLM
STAT- MEDLINE
DCOM- 20080331
LR  - 20210308
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 6
DP  - 2008 Feb 8
TI  - Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows 
      for dissociation of multiple signaling pathways for phagocytosis of apoptotic 
      cells and down-modulation of lipopolysaccharide-inducible NF-kappaB 
      transcriptional activation.
PG  - 3618-3627
LID - S0021-9258(20)69826-X [pii]
LID - 10.1074/jbc.M706906200 [doi]
AB  - Efficient clearance of apoptotic cells is essential for tissue homeostasis, 
      allowing for cellular turnover without inflammatory consequences. The Mer (Nyk 
      and c-Eyk) receptor tyrosine kinase (Mertk) is involved in two aspects of 
      apoptotic cell clearance by acting as a receptor for Gas6, a gamma-carboxylated 
      phosphatidylserine-binding protein that bridges apoptotic and viable cells. 
      First, Mertk acts in a bona fide engulfment pathway in concert with alphavbeta5 
      integrin by regulating cytoskeletal assemblages, and second, it acts as a 
      negative regulator for inflammation by down-modulating pro-inflammatory signals 
      mediated from bacterial lipopolysaccharide-Toll-like receptor 4 (TLR4) signaling, 
      and hence recapitulating anti-inflammatory immune modulation by apoptotic cells. 
      Here we describe Mertk post-receptor events that govern phagocytosis and 
      cytoskeletal signaling are principally mediated by autophosphorylation site 
      Tyr-867. Using the Mertk Y867F mutant and pharmacological inhibitors, we show 
      that Tyr-867 is required for phosphatidylinositol 3-kinase and phospholipase 
      Cgamma2 activation; their activation in turn elicits protein kinase C-dependent 
      signals that act on the actin cytoskeleton. Although Mertk(Y867F) blocked the 
      tyrosine phosphorylation of FAK on Tyr-861 and p130(cas) and also abrogated the 
      phagocytosis of apoptotic cells, this mutant did not suppress 
      lipopolysaccharide-inducible NF-kappaB transcription, nor was NF-kappaB 
      activation dependent on the protein kinase C inhibitor, calphostin C. Finally, 
      unlike the cytoskeletal events associated with Tyr-867 autophosphorylation, the 
      trans-inhibition of NF-kappaB occurred in a postnuclear-dependent fashion 
      independent of cytosolic IkappaB phosphorylation and p65/RelA sequestration. 
      Taken together, these data suggest that Mertk has distinct and separable effects 
      for phagocytosis and for resolving inflammation, providing a molecular rationale 
      for how immune licensing and inflammation can be dissociated from phagocytosis in 
      a single phagocytic receptor.
FAU - Tibrewal, Nitu
AU  - Tibrewal N
AD  - Department of Biochemistry & Molecular Biology, University of Medicine and 
      Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, Newark New Jersey 
      07103.
FAU - Wu, Yi
AU  - Wu Y
AD  - Department of Biochemistry & Molecular Biology, University of Medicine and 
      Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, Newark New Jersey 
      07103.
FAU - D'mello, Veera
AU  - D'mello V
AD  - Department of Biochemistry & Molecular Biology, University of Medicine and 
      Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, Newark New Jersey 
      07103.
FAU - Akakura, Reiko
AU  - Akakura R
AD  - Department of Biochemistry & Molecular Biology, University of Medicine and 
      Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, Newark New Jersey 
      07103.
FAU - George, Thaddeus C
AU  - George TC
AD  - Amnis Corporation, Seattle, Washington 98121.
FAU - Varnum, Brian
AU  - Varnum B
AD  - Inflammation Department, Amgen Pharmaceuticals, Amgen, Inc., Thousand Oaks, 
      California 91320.
FAU - Birge, Raymond B
AU  - Birge RB
AD  - Department of Biochemistry & Molecular Biology, University of Medicine and 
      Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, Newark New Jersey 
      07103. Electronic address: birgera@umdnj.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071126
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Naphthalenes)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (MERTK protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (c-Mer Tyrosine Kinase)
RN  - I271P23G24 (calphostin C)
SB  - IM
MH  - Apoptosis
MH  - Cytoskeleton/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Lipopolysaccharides/*metabolism
MH  - Models, Biological
MH  - NF-kappa B/*metabolism
MH  - Naphthalenes/pharmacology
MH  - Phagocytosis
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins/*chemistry/*metabolism
MH  - Receptor Protein-Tyrosine Kinases/*chemistry/*metabolism
MH  - Signal Transduction
MH  - *Transcriptional Activation
MH  - Tyrosine/*chemistry
MH  - c-Mer Tyrosine Kinase
EDAT- 2007/11/28 09:00
MHDA- 2008/04/01 09:00
CRDT- 2007/11/28 09:00
PHST- 2007/11/28 09:00 [pubmed]
PHST- 2008/04/01 09:00 [medline]
PHST- 2007/11/28 09:00 [entrez]
AID - S0021-9258(20)69826-X [pii]
AID - 10.1074/jbc.M706906200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Feb 8;283(6):3618-3627. doi: 10.1074/jbc.M706906200. Epub 2007 
      Nov 26.