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uPAR's signaling two step

uPAR only needs to bind to vitronectin in the matrix to prompt cells to extend lamellipodia and filopodia.

The uPA receptor (uPAR) is a loner. Jutting from the plasma membrane, it has no apparent connection to the cell interior. But, as Madsen et al. demonstrate on page 927, uPAR induces cells to cling tightly to a surface. The behavior might recruit other receptors and explain how the seemingly isolated uPAR exerts its influence.

Stimulating uPAR galvanizes cells—they attach to a surface, flatten, move, and divide. Cancer cells exploit the receptor's power by cranking up its expression. But based on its structure, uPAR seems like a signaling dead end, and researchers had assumed that uPAR handed off its messages by binding to integrins.

Madsen et al. tested that idea by replacing every amino acid in the receptor one at a time with alanine. They found that cells showed the typical response to uPAR stimulation unless the alanine swap meddled with the receptor segments that bind to vitronectin, a protein in the extracellular matrix. Tampering with uPAR's integrin-binding sites had no impact.

To show that attachment to vitronectin was sufficient for message transmission, the researchers modified cells to make a composite protein. One end sported the membrane-anchoring portion of uPAR, and the other end carried the vitronectin-recognizing stretch of an unrelated matrix-binding protein. The hybrid protein sparked the same effects as uPAR. Together, the results show that lateral interactions between integrins and uPAR aren't essential for relaying signals to the inside of the cell.

Integrins still take part in communication, however. Cells grown on a form of vitronectin that lacked an integrin-binding site ignored uPAR stimulation. Madsen et al. conclude that uPAR signaling occurs in two steps. The receptor first latches onto vitronectin, spurring the cell to snuggle up to the surface. This close contact then promotes liaisons between vitronectin and integrins, which send the messages on their way.

Mitch Leslie

mitchleslie{at}comcast.net

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Related Article

uPAR-induced cell adhesion and migration: vitronectin provides the key

Chris D. Madsen, Gian Maria Sarra Ferraris, Annapaola Andolfo, Orla Cunningham, and Nicolai Sidenius
J. Cell Biol. 2007 177: 927-939. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 951K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Leslie, M. Search for Related Content PubMed Articles by Leslie, M. Related Collections Related Article Social Bookmarking                            What's this?