Seeing muscle evolution

ne heparan sulfate proteoglycan (HSPG) coreceptor is not like another. On page 729, Ding et al. show how two HSPGs, both capable of acting as growth factor coreceptors, have distinct functions on cancer cells. Glypican-1 acts as a long-term growth factor coreceptor, whereas syndecan-1 is shed and helps spread a metasis-promoting proteinase. Upon stimulation with fibroblast growth factor-2 (FGF2), the initial responses of pancreatic cancer cells could be facilitated either by glypican-1 or syndecan-1. Yet the cells rapidly became dependent on glypican-1. The researchers found that the extracellular domain of syndecan-1 was proteolytically clipped off the membrane in response to FGF2. No evidence of glypican-1 cleavage was found. Noncleavable syndecan-1 blocked syndecan-1 shedding and kept cells responsive to FGF2, even in the absence of glypican-1. Stimulation by FGF2 induced activation of matrix metalloproteinase-7 (MMP7), which was responsible for the shedding of the extracellular domain of syndecan-1. Because MMP7 is normally docked on cell surfaces by binding to HSPGs, its activation by FGF2 induced its own release, in association with shed syndecan-1 ectodomains. The team thinks that growth factor–induced release of MMP7–synde-can-1 complexes from tumor cells enhances the ability of MMPs to diffuse out of tumors and degrade surrounding extracellular matrix, an early step in metastasis. MMP7 is know to facilitate metastasis, and recent evidence indicates that forcing tumor cells to shed syndecan-1 constitutively also makes them more aggressive in vivo. O Nonubiquitous autophagy ells use autophagy for bulk degradation, in what is often thought of as a non-specific process. That perception, however , might not be accurate, according to data from Bjørkøy et al. (page 603). Some autophagy substrates are polyubiquitinated and appear to be targeted for destruction. Protein aggregates, such as those found in Huntington's disease, contain polyubiquiti-nated proteins, as well as the polyubiquitin-binding protein p62. The team found that p62 accumulation into protein aggregates depended on its poly-ubiquitin binding domain and on a polymeriza-tion domain, PB1, which allows large chains of p62 to form. p62 also colocalized with LC3, a protein that binds to the autophagosome membrane. Moreover, inhibition of autophagy blocked p62 degradation. In cells expressing a mutant huntingtin protein, aggregates containing p62 and LC3 were even more common than in the HeLa cells initially studied. Reducing the amount of p62 expressed caused a higher proportion of the cells in the population to undergo apoptosis. The data suggest that p62 helps identify substrates for autophagy via its …