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J. Biol. Chem., Vol. 283, Issue 28, 19192-19200, July 11, 2008

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Endothelial Cell Annexin A2 Regulates Polyubiquitination and Degradation of Its Binding Partner S100A10/p11^*

Kai-Li He, Arunkumar B. Deora, Huabao Xiong, Qi Ling, Babette B. Weksler^¶, Ruben Niesvizky^¶, and Katherine A. Hajjar¹

From the Departments of Cell and Developmental Biology and ^¶Medicine, Weill Cornell Medical College, New York, New York 10065 and the Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029

The annexin A2 (A2) heterotetramer, consisting of two copies of A2 and two copies of S100A10/p11, promotes fibrinolytic activity on the surface of vascular endothelial cells by assembling plasminogen and tissue plasminogen activator (tPA) and accelerating the generation of plasmin. In humans, overexpression of A2 by acute promyelocytic leukemia cells is associated with excessive fibrinolysis and hemorrhage, whereas anti-A2 autoantibodies appear to accentuate the risk of thrombosis in patients with anti-phospholipid syndrome. Complete deficiency of A2 in mice leads to a lack of tPA cofactor activity, accumulation of intravascular fibrin, and failure to clear arterial thrombi. Within the endothelial cell, p11 is required for Src kinase-mediated tyrosine phosphorylation of A2, which signals translocation of both proteins to the cell surface. Here we show that p11 is expressed at very low levels in the absence of A2 both in vitro and in vivo. We demonstrate further that unpartnered p11 becomes polyubiquitinated and degraded via a proteasome-dependent mechanism. A2 stabilizes intracellular p11 through direct binding, thus masking an autonomous p11 polyubiquitination signal that triggers proteasomal degradation. This interaction requires both the p11-binding N-terminal domain of A2 and the C-terminal domain of p11. This mechanism prevents accumulation of free p11 in the endothelial cell and suggests that regulation of tPA-dependent cell surface fibrinolytic activity is precisely tuned to the intracellular level of p11.

Received for publication, January 4, 2008 , and in revised form, March 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL42493, HL46403, and HL67839. This work was also supported by March of Dimes Grant 6-FY05-94. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

¹ To whom correspondence should be addressed: Box 45, Weill Cornell Medical College, 1300 York Ave., New York, NY 10065. Fax: 212-746-8809; E-mail: khajjar{at}med.cornell.edu.

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