Integrin trafficking, including internalization, recycling, and lysosomal degradation, is crucial for the regulation of cellular functions. Exosomes, nano-sized extracellular vesicles, are believed to play important roles in intercellular communications. This study demonstrates that exosomes released from human macrophages negatively regulate endothelial cell migration through control of integrin trafficking. Macrophage-derived exosomes promote internalization of integrin β1 in primary HUVECs. The internalized integrin β1 persistently accumulates in the perinuclear region and is not recycled back to the plasma membrane. Experimental results indicate that macrophage-derived exosomes stimulate trafficking of internalized integrin β1 to lysosomal compartments with a corresponding decrease in the integrin destined for recycling endosomes, resulting in proteolytic degradation of the integrin. Moreover, ubiquitination of HUVEC integrin β1 is enhanced by the exosomes, and exosome-mediated integrin degradation is blocked by bafilomycin A, a lysosomal degradation inhibitor. Macrophage-derived exosomes were also shown to effectively suppress collagen-induced activation of the mitogenactivated protein kinase/extracellular signal-regulated kinase signaling pathway and HUVEC migration, which are both dependent on integrin β1. These observations provide new insight into the functional significance of exosomes in the regulation of integrin trafficking. Keywords: Endothelial cell migration r Exosomes r Integrin trafficking r MacrophagesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIntegrin, a heterodimeric transmembrane receptor composed of α-and β-subunits, has a fundamental role in communication between cells and the extracellular matrix [1,2]. Recent studies have shown that trafficking of integrin is a crucial step in this communication [3][4][5]. Integrin is regularly internalized via the endocytosis pathway and internalized integrin is recycled back to the plasma membrane [3,4]. Internalized integrin β1, the most widely expressed integrin subunit, accumulates in the perinuclear Correspondence: Dr. Doo-Sik Kim e-mail: dskim@yonsei.ac.kr region of cells and is returned to the plasma membrane through RAB11-positive recycling endosomes [3]. The recycling process rearranges the distribution of integrins on the cell surface and controls the direction of cell migration [3]. Ubiquitination of integrin acts as a signal to trigger trafficking of internalized integrin to the lysosomal degradation compartment [5,6]. The degradation process is important for controlling the proper expression level of integrin on the cell surface, by which cell-matrix association and cell migration are tightly regulated [5,7].Integrin is a key regulator of cellular functions associated with vascular processes [8,9]. Endothelial cell migration and leukocyte recruitment during inflammation are tightly controlled by integrin functions. The expression and activation of integrins C...

Background: Cell migration is involved in altering the cell and matrix interface on the cell surface. Results: ␤ig-h3 is cleaved by MMP-9, and its cleavage results in changes in its binding properties, cell adhesion, cell migration, FAK/Src signals, and chemoattractant effects. Conclusion: MMP-9-cleaved ␤ig-h3 modulates tumor cell and macrophage migration. Significance: The MMP-9-mediated ␤ig-h3 processing mechanism is crucial for understanding cell migration.

A disintegrin and metalloproteinase 15 (ADAM15), the only ADAM protein containing an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain, is a widely expressed membrane protein that is involved in tumor progression and suppression. However, the underlying mechanism of ADAM15-mediated tumor suppression is not clearly understood. This study demonstrates that ADAM15 is released as an exosomal component, and ADAM15 exosomes exert tumor suppressive activities. We found that exosomal ADAM15 release is stimulated by phorbol 12-myristate 13-acetate, a typical protein kinase C activator, in various tumor cell types, and this results in a corresponding decrease in plasma membrane-associated ADAM15. Exosomes rich in ADAM15 display enhanced binding affinity for integrin αvβ3 in an RGD-dependent manner and suppress vitronectin- and fibronectin-induced cell adhesion, growth, and migration, as well as in vivo tumor growth. Exosomal ADAM15 is released from human macrophages, and macrophage-derived ADAM15 exosomes have tumor inhibitory effects. This work suggests a primary role of ADAM15 for exosome-mediated tumor suppression, as well as functional significance of exosomal ADAM protein in antitumor immunity.

Abstract. We consider frames in a finite-dimensional Hilbert space H n where frames are exactly the spanning sets of the vector space. The diagram vector of a vector in R 2 was previously defined using polar coordinates and was used to characterize tight frames in R 2 in a geometric fashion. Reformulating the definition of a diagram vector in R 2 we provide a natural extension of this notion to R n and C n . Using the diagram vectors we give a characterization of tight frames in R n or C n . Further we provide a characterization of when a unit-norm frame in R n or C n can be scaled to a tight frame. This classification allows us to determine all scaling coefficients that make a unit-norm frame into a tight frame. Mathematics subject classification (2010): 42C15, 05B20, 15A03.

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