Potential Role of Kringle-Integrin Interaction in Plasmin and uPA Actions (A Hypothesis)

Yoshikazu Takada

doi:10.1155/2012/136302

Abstract

We previously showed that the kringle domains of plasmin and angiostatin, the N-terminal four kringles (K1–4) of plasminogen, directly bind to integrins. Angiostatin blocks tumor-mediated angiogenesis and has great therapeutic potential. Angiostatin binding to integrins may be related to the antiinflammatory action of angiostatin. We reported that plasmin induces signals through protease-activated receptor (PAR-1), and plasmin-integrin interaction may be required for enhancing plasmin concentration on the cell surface, and enhances its signaling function. Angiostatin binding to integrin does not seem to induce proliferative signals. One possible mechanism of angiostatin's inhibitory action is that angiostatin suppresses plasmin-induced PAR-1 activation by competing with plasmin for binding to integrins. Interestingly, plasminogen did not interact with αvβ3, suggesting that the αvβ3-binding sites in the kringle domains of plasminogen are cryptic. The kringle domain of urokinase-type plasminogen activator (uPA) also binds to integrins. The uPA-integrin interaction enhances uPA concentrations on the cell surface and enhances plasminogen activation on the cell surface. It is likely that integrins bind to the kringle domain, and uPAR binds to the growth factor-like domain (GFD) of uPA simultaneously, making the uPAR-uPA-integrin ternary complex. We present a docking model of the ternary complex.

Highlights

The integrins are a superfamily of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands
We found that bovine arterial endothelial (BAE) cells adhere to angiostatin in an integrin-dependent manner and Journal of Biomedicine and Biotechnology that integrins αvβ3, α9β1, and to a lesser extent α4β1, bind to angiostatin. αvβ3 is a predominant receptor for angiostatin on BAE cells, since a function-blocking antibody to αvβ3 effectively blocks adhesion of BAE cells to angiostatin, but an antibody to α9β1 does not. ε-Aminocaproic acid, a Lys analogue, effectively blocks angiostatin binding to BAE cells, indicating that an unoccupied Lys-binding site of the kringles may be required for integrin binding
Angiostatin, representing the kringle domains of plasmin, alone did not induce the migration of α9-CHO cells, but simultaneous activation of the G proteincoupled protease-activated receptor (PAR)-1 with an agonist peptide induced the migration on angiostatin, whereas PAR2 or PAR-4 agonist peptides were without effect

Summary

Yoshikazu Takada

A small chemical inhibitor of PAR-1 (RWJ 58259) and a palmitoylated PAR-1-blocking peptide inhibited plasmininduced migration of α9-CHO cells These results suggest that plasmin induces migration by kringle-mediated binding to α9β1 and simultaneous proteolytic activation of PAR-1 [10]. Plasminogen does not interact with integrins αvβ or α9β1 (possibly the integrin-binding sites are cryptic in plasminogen) (Figure 1) Based on our results on the plasmin kringle-integrin interaction, we hypothesized that the kringle domains of other serine proteases may interact with integrins and the interaction may play a role in their functions Consistent with this idea, kringle domains from other proteins such as tissue-type plasminogen activator (tPA) [14] and apolipoprotein [15] have been reported to interact with integrins.

Serine protease inhibitors PAR antagonists

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