Document Detail


CIB1 deficiency results in impaired thrombosis: the potential role of CIB1 in outside-in signaling through integrin alpha IIb beta 3.
MedLine Citation:
PMID:  19691476     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Agonist-induced inside-out signaling activates platelet integrin alpha(IIb)beta(3), rendering it to bind plasma fibrinogen (Fg). Fg binding induces outside-in signaling that culminates in platelet aggregation, leading to physiological hemostasis and pathological thrombosis. How outside-in signaling through alpha(IIb)beta(3) regulates hemostasis and thrombosis is not well understood. We have previously shown that CIB1 is involved in regulating alpha(IIb)beta(3) function. OBJECTIVE: To determine the in vivo role of CIB1 in the process of hemostasis and thrombosis. METHODS AND RESULTS: Genetic ablation of Cib1 significantly increased mouse tail bleeding time. Greater than 50% of the Cib1 null mice showed a rebleeding phenotype. Time taken for complete occlusion of carotid artery upon 10% FeCl(3)-induced injury was significantly delayed in the absence of Cib1. This was also associated with unstable thrombus formation. The inside-out signaling appears normal as ADP-, collagen- and PAR4 peptide-induced aggregation and fibrinogen binding was unaffected. The absence of Cib1 also affected the ability of platelets to spread on immobilized Fg, but not filopodia formation. Spreading could be restored in Cib1 null platelets by the addition of exogenous ADP. Outside-in signaling-dependent tyrosine phosphorylation of the integrin beta(3) subunit was significantly reduced in the absence of Cib1 as determined by Western blot analysis. CONCLUSION: Using gene knockout mice, we show for the first time that lack of Cib1 results in impaired thrombosis. CIB1 regulates these processes by affecting platelet spreading, but not platelet filopodia formation. These in vivo and in vitro results clearly show that CIB1 is a key regulator of thrombosis.
Authors:
M U Naik; A Nigam; P Manrai; P Millili; K Czymmek; M Sullivan; U P Naik
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-08-19
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  7     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-12-17     Completed Date:  2010-03-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  England    
Other Details:
Languages:  eng     Pagination:  1906-14     Citation Subset:  IM    
Affiliation:
Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA. unaik@udel.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Platelets / pathology
Calcium-Binding Proteins / deficiency*,  physiology*
Cell Shape
Fibrinogen / metabolism
Hemostasis
Mice
Mice, Knockout
Platelet Adhesiveness
Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
Signal Transduction*
Thrombosis / etiology*,  pathology
Grant Support
ID/Acronym/Agency:
HL57630/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Calcium-Binding Proteins; 0/Cib1 protein, mouse; 0/Platelet Glycoprotein GPIIb-IIIa Complex; 9001-32-5/Fibrinogen

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