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Characterization of a Novel Integrin Binding Protein, VPS33B, Which Is Important for Platelet Activation and In Vivo Thrombosis and Hemostasis.


ABSTRACT: Integrins are heterodimeric (?/?) membrane proteins that play fundamental roles in many biological processes, for example, cell adhesion and spreading, which are important for platelet function and hemostasis. The molecular mechanism that regulates integrin activation is not completely understood.Here, we show that VPS33B, a member of the Sec1/Munc18 family, binds directly to the integrin ? subunit. Overexpression of VPS33B in Chinese hamster ovary cells potentiated ?IIb?3 outside-in signaling but not inside-out signaling. Platelets, from megakaryocyte- and platelet-specific VPS33B conditional knockout mice, had normal morphology, yet their spreading on fibrinogen was impaired and they failed to support clot retraction. Platelet aggregation and ATP secretion in response to low-dose agonists were reduced in the VPS33B knockout mice. ?IIb?3-mediated endocytosis of fibrinogen was also defective. Tail bleeding times and times to occlusion in an FeCl3-induced thrombosis model were prolonged in the VPS33B knockout mice. Furthermore, VPS33B acted upstream of the RhoA-ROCK-MLC and Rac1-dependent pathways that lead to clot retraction and cell spreading, respectively.Our work demonstrates that vesicular trafficking complexes, containing VPS33B, are a novel class of modifiers of integrin function. Our data also provide insights into the molecular mechanism and treatment of arthrogryposis, renal dysfunction, and cholestasis syndrome.

SUBMITTER: Xiang B 

PROVIDER: S-EPMC4679702 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Characterization of a Novel Integrin Binding Protein, VPS33B, Which Is Important for Platelet Activation and In Vivo Thrombosis and Hemostasis.

Xiang Binggang B   Zhang Guoying G   Ye Shaojing S   Zhang Rui R   Huang Cai C   Liu Jun J   Tao Min M   Ruan Changgeng C   Smyth Susan S SS   Whiteheart Sidney W SW   Li Zhenyu Z  

Circulation 20150923 24


<h4>Background</h4>Integrins are heterodimeric (α/β) membrane proteins that play fundamental roles in many biological processes, for example, cell adhesion and spreading, which are important for platelet function and hemostasis. The molecular mechanism that regulates integrin activation is not completely understood.<h4>Methods and results</h4>Here, we show that VPS33B, a member of the Sec1/Munc18 family, binds directly to the integrin β subunit. Overexpression of VPS33B in Chinese hamster ovary  ...[more]

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