Characterization of calcium- and integrin-binding protein 1 (CIB1) knockout platelets: Potential compensation by CIB family members

Jan C. DeNofrio; Weiping Yuan; Brenda R. Temple; Holly R. Gentry; Leslie V. Parise

doi:10.1160/TH08-06-0351

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 100(05): 847-856
DOI: 10.1160/TH08-06-0351

Platelets and Blood Cells

Schattauer GmbH

Characterization of calcium- and integrin-binding protein 1 (CIB1) knockout platelets: Potential compensation by CIB family members

Jan C. DeNofrio^*

¹Curriculum in Genetics and Molecular Biology

,

Weiping Yuan^*

² Department of Biochemistry and Biophysics

,

Brenda R. Temple

² Department of Biochemistry and Biophysics

,

Holly R. Gentry

² Department of Biochemistry and Biophysics

,

Leslie V. Parise

¹Curriculum in Genetics and Molecular Biology

² Department of Biochemistry and Biophysics

³Department of Pharmacology

⁴ Lineberger Comprehensive Cancer Center

⁵Carolina Cardiovascular Biology Center, The University of North Carolina, Chapel Hill, North Carolina, USA

› Institutsangaben

Abstract

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Summary

Platelet aggregation requires activation of the αIIbβ3 integrin,an event regulated by the integrin cytoplasmic tails. CIB1 binds to the cytoplasmic tail of the integrin αIIb subunit. Previous overexpression and knockdown studies in murine megakaryocytes demonstrated that CIB1 inhibits integrin αIIbβ3 activation.Here we analyzed Cib1^-/- mice to determine the function of CIB1 in platelets in vitro and in vivo. We found that although these mice had no overt platelet phenotype, mRNA level of CIB1 homolog CIB3 was increased in Cib1^-/- megakaryocytes. In vitro binding experiments showed that recombinant CIB1, -2 and -3 bound specifically to an αIIb cytoplasmic tail peptide. Subsequent protein modeling experiments indicated that CIBs 1–3 each have a highly conserved hydrophobic binding pocket. Therefore, the potential exists for compensation for the loss of CIB1 by these CIB family members, thereby preventing pathologic thrombus formation in Cib1^-/- mice.

Keywords

CIB1 - platelet - integrin αIIbβ3 activation - aggregation - knockout mouse - compensation

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Referenzen

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