Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins.

Abstract

Fibroblasts from patients with pulmonary fibrosis express higher levels of the receptor for urokinase, and the extent of fibrosis in some animal models exhibits a dependence on the urokinase receptor. Recent observations have identified the urokinase receptor as a trans-interacting receptor with consequences on signaling and cell responses that vary depending on its interacting partner, the relative levels of expression, and the state of cellular transformation. We undertook this study to define the urokinase-type plasminogen activator cellular receptor (u-PAR)-integrin interactions and to determine the functional consequences of such interactions on normal human lung fibroblast attachment and migration. u-PAR colocalizes in lammelipodia/filopodia with relevant integrins that mediate fibroblast attachment and spreading on the provisional matrix proteins vitronectin, fibronectin, and collagens. Inhibitory antibody studies have revealed that human lung fibroblasts utilize alpha(v)beta(5) to attach to vitronectin, predominantly alpha(5)beta(1) (and alpha(v)beta(3)) to attach to fibronectin, and alpha(1)beta(1), alpha(2)beta(1), and alpha(3)beta(1) to attach to collagen. Blocking studies with alpha-integrin subunit decoy peptides and u-PAR neutralizing antibodies indicate that u-PAR modulates the integrin-mediated attachment to purified provisional matrix proteins, to anti-integrin antibodies, or to fibroproliferative lesions from fibrotic lungs. Furthermore, these decoy peptides blunt fibroblast spreading and migration. We show that u-PAR can interact with multiple alpha-integrins but with a preference for alpha(3). Taken together, these data demonstrate that u-PAR may interact with multiple integrins in normal human lung fibroblasts thereby promoting attachment, spreading, and migration. Modulation of fibroblast invasion would be expected to lead to amelioration of fibroproliferative diseases of the lung.

• Authors: Sha Zhu, Candece L Gladson, Kimberly E White, Qiang Ding, Jerry Stewart Jr, Tong H Jin, Harold A Chapman Jr, Mitchell A Olman
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 297 Issue 1 Pg. L97-108 (Jul 2009) ISSN: 1522-1504 [Electronic] United States
• PMID: 19411312 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Extracellular Matrix Proteins
• Fibronectins
• Integrins
• Protein Subunits
• Receptors, Urokinase Plasminogen Activator
• Vitronectin
• Fibrinogen
• Collagen

Topics

• Adult
• Animals
• Cattle
• Cell Adhesion
• Cell Movement
• Cell Surface Extensions (metabolism)
• Collagen (metabolism)
• Extracellular Matrix Proteins (metabolism)
• Fibrinogen (metabolism)
• Fibroblasts (cytology, metabolism)
• Fibronectins (metabolism)
• Fibrosis (pathology)
• Humans
• Integrins (metabolism)
• Lung (cytology)
• Mice
• Protein Binding
• Protein Subunits (metabolism)
• Protein Transport
• Receptors, Urokinase Plasminogen Activator (metabolism)
• Vitronectin (metabolism)
• Wound Healing