Identification of a Urokinase Receptor-Integrin Interaction Site

Simon, Daniel I.; Wei, Ying; Zhang, Li; Rao, Navaneetha K.; Xu, Huiyun; Chen, Zhiping; Liu, Qiumei; Rosenberg, Steven; Chapman, Harold A.

doi:10.1074/jbc.275.14.10228

Cited by 189 publications

(179 citation statements)

References 33 publications

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“…Functional uPA/uPAR/integrin association modulates various aspects of cell physiology such as motility, mitogenic activity or adhesive phenotype. At the molecular level, uPAR interacts with at least two distinct regions of the integrin molecule -the lectin domain48 and a site at the interface of α-and β-chains that is close to, but distinct from, the "classical" MIDAS integrin binding site47 , 49. Binding of uPA to uPAR typically strengthens uPAR-integrin interactions and could elicit the integrin-mediated signaling, but the mechanisms underlying these phenomenona are not clear.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis of Interaction between Urokinase-type Plasminogen Activator and its Receptor

Bařinka

Parry²,

Callahan³

et al. 2006

Journal of Molecular Biology

108

116

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SummaryRecent studies indicate that binding of urokinase-type plasminogen activator (uPA) to its high affinity receptor (uPAR), orchestrates uPAR interactions with other cellular components that play a pivotal role in diverse (patho-)physiological processes including wound healing, angiogenesis, inflammation, and cancer metastasis. However, notwithstanding the wealth of biochemical data available describing the activities of uPAR, little is known as to the exact mode of uPAR-uPA interactions and the presumed conformational changes that accompanying uPA-uPAR engagement. Here we report the crystal structure of soluble urokinase plasminogen activator receptor (suPAR), which contains the three domains of the wild-type receptor but lacks the cell surface anchoring sequence, in complex with the amino terminal fragment of urokinase-type plasminogen activator (ATF), at the resolution of 2.8 Å. We also report the 1.9 Å crystal structure of the free ATF. Our results provide a structural basis, represented by conformational changes induced in uPAR, for several published biochemical observations describing the nature of uPARuPA interactions and provide insight into mechanisms that may be responsible for the cellular responses induced by uPA binding.

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Section: Discussionmentioning

confidence: 99%

Structural Basis of Interaction between Urokinase-type Plasminogen Activator and its Receptor

Bařinka

Parry²,

Callahan³

et al. 2006

Journal of Molecular Biology

108

116

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“…However, the peptide M25 identified by phage display [118] has homology to the integrin α M and inhibits the binding of uPA to uPAR [119]. It inhibits leukocyte adhesion to fibrinogen, vitronectin, and endothelial cells.…”

Section: Inhibition Of Upa-integrin Interactionsmentioning

confidence: 99%

Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

119

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New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

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“…The uPA/uPAR system has been extensively studied and its diverse functions generate a complexity strictly dependent on the microenvironment and presence of cofactors (Hoyer-Hansen et al, 1992;Simon et al, 2000;Liu et al, 2002;Ustach and Kim, 2005). On account of its low zymogenic activity, single-chain (sc) uPA is usually referred to as a 53 kDa pro-enzyme.…”

Section: Introductionmentioning

confidence: 99%

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

Ehnman

Fredriksson

et al. 2008

Oncogene

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Members of the platelet-derived growth factor (PDGF) family are mitogens for cells of mesenchymal origin and have important functions during embryonic development, blood vessel maturation, fibrotic diseases and cancer. In contrast to the two classical PDGFs, the novel and less well-characterized members, PDGF-CC and PDGF-DD, are latent factors that need to be processed extracellularly by activating proteases, before they can mediate PDGF receptor activation. Here, we elucidate the structural requirements for urokinase plasminogen activator (uPA)-mediated activation of PDGF-DD, as well as the intricate interplay with uPA receptor (uPAR) signalling. Furthermore, we show that activated PDGF-DD, in comparison to latent, more potently transforms NIH/3T3 cells in vitro. Conversely, xenograft studies in nude mice demonstrate that cells expressing latent PDGF-DD are more tumorigenic than those expressing activated PDGF-DD. These findings imply that a fine-tuned proteolytic activation, in the local milieu, controls PDGF-DD bioavailability. Moreover, we suggest that proteolytic activation of PDGF-DD reveals a retention motif mediating interactions with pericellular components. Our proposed mechanism, where uPA not only generates active PDGF-DD, but also regulates its spatial distribution, provides novel insights into the biological function of PDGF-DD.

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Identification of a Urokinase Receptor-Integrin Interaction Site

Cited by 189 publications

References 33 publications

Structural Basis of Interaction between Urokinase-type Plasminogen Activator and its Receptor

Structural Basis of Interaction between Urokinase-type Plasminogen Activator and its Receptor

Role of plasminogen activator-plasmin system in tumor angiogenesis

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

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