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Liberating TGFß

Only particular fibrillin-1 fragments activate TGFß signaling.

Overactive TGFß spurs Marfan's syndrome, which might have been responsible for Abraham Lincoln's rangy physique. But how the molecule gets released from storage and switched on is uncertain. On page 355 Chaudhry et al. fill in a key step, showing that a piece of an extracellular matrix (ECM) protein frees inert TGFß.

TGFß helps control whether cells move, divide, specialize, and survive. Cells often lock up the potent cytokine by fastening a complex containing its inactive form to fibrillin-1 fibers in the ECM. Discovering how this sequestered TGFß breaks loose might clarify the mechanism of Marfan's syndrome, in which fibrillin-1 mutations lead to symptoms such as a weakened aorta and leaky heart valves.

Chaudhry et al. demonstrated that fibrillin-1 itself helps release the TGFß complex. The researchers narrowed this ability to a small fragment of the protein. The segment doesn't bind to TGFß. Instead, it attaches tightly to the end of fibrillin-1 that carries the cytokine complex. The researchers hypothesize that this interaction alters the shape of full-length fibrillin-1 and dislodges the inert TGFß. Other enzymes could then activate it.

Fibrillin fragments wouldn't normally be loose in the extracellular matrix, but some fibrillin mutations distort the protein so that it is more likely to be sliced up by ECM enzymes. That might unleash the TGFß-releasing segment, the researchers speculate.

Mitch Leslie

mitchleslie{at}comcast.net

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Related Article

Fibrillin-1 regulates the bioavailability of TGFß1

Shazia S. Chaudhry, Stuart A. Cain, Amanda Morgan, Sarah L. Dallas, C. Adrian Shuttleworth, and Cay M. Kielty
J. Cell Biol. 2007 176: 355-367. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 903K) 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?