Faculty Collaboration Database

Kindlin-2 regulates hemostasis by controlling endothelial cell-surface expression of ADP/AMP catabolic enzymes via a clathrin-dependent mechanism. Blood 2013 Oct 03;122(14):2491-9

Date

07/31/2013

Pubmed ID

23896409

Pubmed Central ID

PMC3790514

DOI

10.1182/blood-2013-04-497669

Scopus ID

2-s2.0-84887629722 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice. In the present study, we tested whether hemostasis might be perturbed in kindlin-2(+/-) mice. Bleeding time and carotid artery occlusion time were significantly prolonged in kindlin-2(+/-) mice. Whereas plasma concentrations/activities of key coagulation/fibrinolytic proteins and platelet counts and aggregation were similar in wild-type and kindlin-2(+/-) mice, kindlin-2(+/-) endothelial cells (ECs) showed enhanced inhibition of platelet aggregation induced by adenosine 5'-diphosphate (ADP) or low concentrations of other agonists. Cell-surface expression of 2 enzymes involved in ADP/adenosine 5'-monophosphate (AMP) degradation, adenosine triphosphate (ATP) diphosphohydrolase (CD39) and ecto-5'-nucleotidase (CD73) were increased twofold to threefold on kindlin-2(+/-) ECs, leading to enhanced ATP/ADP catabolism and production of adenosine, an inhibitor of platelet aggregation. Trafficking of CD39 and CD73 at the EC surface was altered in kindlin-2(+/-) mice. Mechanistically, this was attributed to direct interaction of kindlin-2 with clathrin heavy chain, thereby controlling endocytosis and recycling of CD39 and CD73. The interaction of kindlin-2 with clathrin was independent of its integrin binding site but still dependent on a site within its F3 subdomain. Thus, kindlin-2 regulates trafficking of EC surface enzymes that control platelet responses and hemostasis.

Author List

Pluskota E, Ma Y, Bledzka KM, Bialkowska K, Soloviev DA, Szpak D, Podrez EA, Fox PL, Hazen SL, Dowling JJ, Ma YQ, Plow EF

Author

Yan-Qing Ma PhD Associate Investigator in the Blood Research Institute department at BloodCenter of Wisconsin

MESH terms used to index this publication - Major topics in bold

5'-Nucleotidase
Adenosine Diphosphate
Adenosine Monophosphate
Animals
Antigens, CD
Apyrase
Blood Platelets
Cell Membrane
Clathrin
Cytoskeletal Proteins
Endothelial Cells
Female
Flow Cytometry
Hemostasis
Immunoprecipitation
Male
Mice
Mice, Knockout
Muscle Proteins
Platelet Aggregation
Protein Transport
Surface Plasmon Resonance