title: CIB1 is an endogenous inhibitor of agonist-induced integrin alphaIIbbeta3 activation.
abstract: In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation.
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.forename: Tina M
authors.initials: TM
authors.lastname: Leisner
authors.forename: Andrew W
authors.initials: AW
authors.lastname: McFadden
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Wang
authors.forename: Mark K
authors.initials: MK
authors.lastname: Larson
authors.forename: Shantres
authors.initials: S
authors.lastname: Clark
authors.forename: Christel
authors.initials: C
authors.lastname: Boudignon-Proudhon
authors.forename: Stephen C-T
authors.initials: SC
authors.lastname: Lam
authors.forename: Leslie V
authors.initials: LV
authors.lastname: Parise
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D016608:Talin / Q000378:metabolism
chemical_list: C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016608:Talin; D005340:Fibrinogen