Document Detail


Immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated inhibitory signaling is regulated by sequential phosphorylation mediated by distinct nonreceptor tyrosine kinases: a case study involving PECAM-1.
MedLine Citation:
PMID:  23418871     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The activation state of many blood and vascular cells is tightly controlled by a delicate balance between receptors that contain immunoreceptor tyrosine-based activation motifs (ITAMs) and those that contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Precisely how the timing of cellular activation by ITAM-coupled receptors is regulated by ITIM-containing receptors is, however, poorly understood. Using platelet endothelial cell adhesion molecule 1 (PECAM-1) as a prototypical ITIM-bearing receptor, we demonstrate that initiation of inhibitory signaling occurs via a novel, sequential process in which Src family kinases phosphorylate the C-terminal ITIM, thereby enabling phosphorylation of the N-terminal ITIM of PECAM-1 by other Src homology 2 domain-containing nonreceptor tyrosine kinases (NRTKs). NRTKs capable of mediating the second phosphorylation event include C-terminal Src kinase (Csk) and Bruton's tyrosine kinase (Btk). Btk and Csk function downstream of phosphatidylinositol 3-kinase (PI3K) activation during ITAM-dependent platelet activation. In ITAM-activated platelets that were treated with a PI3K inhibitor, PECAM-1 was phosphorylated but did not bind the tandem SH2 domain-containing tyrosine phosphatase SHP-2, indicating that it was not phosphorylated on its N-terminal ITIM. Csk bound to and phosphorylated PECAM-1 more efficiently than did Btk and required its SH2 domain to perform these functions. Additionally, the phosphorylation of the N-terminal ITIM of Siglec-9 by Csk is enhanced by the prior phosphorylation of its C-terminal ITIM, providing evidence that the ITIMs of other dual ITIM-containing receptors are also sequentially phosphorylated. On the basis of these findings, we propose that sequential ITIM phosphorylation provides a general mechanism for precise temporal control over the recruitment and activation of tandem SH2 domain-containing tyrosine phosphatases that dampen ITAM-dependent signals.
Authors:
Benjamin E Tourdot; Michelle K Brenner; Kathleen C Keough; Trudy Holyst; Peter J Newman; Debra K Newman
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-03
Journal Detail:
Title:  Biochemistry     Volume:  52     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-16     Completed Date:  2013-07-25     Revised Date:  2014-04-17    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2597-608     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amino Acid Motifs
Antigens, CD31 / metabolism*
Blood Platelets / metabolism*
Cytoplasm / metabolism
Humans
Phosphopeptides / metabolism
Phosphorylation
Platelet Membrane Glycoproteins / metabolism
Protein Structure, Tertiary
Protein-Tyrosine Kinases / metabolism
Signal Transduction*
src Homology Domains
src-Family Kinases / metabolism
Grant Support
ID/Acronym/Agency:
HL40926/HL/NHLBI NIH HHS; HL90883/HL/NHLBI NIH HHS; P01 HL044612/HL/NHLBI NIH HHS; R01 HL040926/HL/NHLBI NIH HHS; R01 HL090883/HL/NHLBI NIH HHS; UL1 TR000055/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD31; 0/Phosphopeptides; 0/Platelet Membrane Glycoproteins; 0/platelet membrane glycoprotein VI; EC 2.7.10.1/Agammaglobulinaemia tyrosine kinase; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.2/CSK tyrosine-protein kinase; EC 2.7.10.2/lyn protein-tyrosine kinase; EC 2.7.10.2/src-Family Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Predictors for positive surgical margins after robot-assisted radical prostatectomy: A single surgeo...
Next Document:  The Potential Role of Curcumin and Taurine Combination Therapy on human myeloid Leukemic cells Propa...