An Essential Role for Ectodomain Shedding in Mammalian Development

Peschon, Jacques J.; Slack, Jennifer L.; Reddy, P. Madhusudhana; Stocking, Kim L.; Sunnarborg, Susan W.; Lee, Dong Hoon; Russell, William E.; Castner, Beverly J.; Johnson, Richard S.; Fitzner, Jeffrey N.; Boyce, Rogely; Nelson, Nicole; Kozlosky, Carl J.; Wolfson, Martin F.; Rauch, Charles T.; Cerretti, Douglas Pat; Paxton, Raymond J.; March, Carl J.; Black, Roy A.

doi:10.1126/science.282.5392.1281

Cited by 1,498 publications

(1,545 citation statements)

References 38 publications

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“…APP, Delta and TGFα have been characterized genetically, cell biologically, and in vitro with pure proteins as non-substrates for rhomboid enzymes (Peschon et al, 1998; Urban and Freeman, 2003; Lemberg et al, 2005; Urban and Wolfe, 2005; Adrain et al, 2011). We reasoned that incorporating a single proline, which has the highest helix-and-membrane exit propensity of all residues (Monné et al, 1999a, 1999b), might increase their intrinsic TM dynamics.…”

Section: Resultsmentioning

confidence: 99%

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Moin

Urban

2012

eLife

119

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Rhomboid proteases reside within cellular membranes, but the advantage of this unusual environment is unclear. We discovered membrane immersion allows substrates to be identified in a fundamentally-different way, based initially upon exposing ‘masked’ conformational dynamics of transmembrane segments rather than sequence-specific binding. EPR and CD spectroscopy revealed that the membrane restrains rhomboid gate and substrate conformation to limit proteolysis. True substrates evolved intrinsically-unstable transmembrane helices that both become unstructured when not supported by the membrane, and facilitate partitioning into the hydrophilic, active-site environment. Accordingly, manipulating substrate and gate dynamics in living cells shifted cleavage sites in a manner incompatible with extended sequence binding, but correlated with a membrane-and-helix-exit propensity scale. Moreover, cleavage of diverse non-substrates was provoked by single-residue changes that destabilize transmembrane helices. Membrane immersion thus bestows rhomboid proteases with the ability to identify substrates primarily based on reading their intrinsic transmembrane dynamics.DOI: http://dx.doi.org/10.7554/eLife.00173.001

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Section: Resultsmentioning

confidence: 99%

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Moin

Urban

2012

eLife

119

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“…We next investigated the possibility that the increased activation of EGFR and ErbB-2 induced by ADAMTS-1 is achieved through shedding/activating the transmembrane precursors of these GFs, the ligands of ErbB receptor tyrosine kinases. The EGF family GFs include EGF, transforming growth factor-a (TGF-a), HB-EGF, AR, betacellulin, epiregulin, neuregulin, and epigen (Massague´and Pandiella, 1993;Harris et al, 2003); all of these are shed from the cell surface (Peschon et al, 1998;Lee et al, 2003;Sahin et al, 2004). Increasing evidence suggests that shedding of EGF family GF precursors regulates the availability and bioactivity of these factors and is essential for the activation of the ErbB-signaling pathways Jackson et al, 2003;Lee et al, 2003;Yamazaki et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…Although the functional differences between mature soluble EGF family GFs and their transmembrane precursors have not been well-established, the phenotypic similarities between TGF-a-and ADAM17-null mice and between HB-EGF-null and HB-EGF cleavageresistant mice clearly suggest that shedding of these precursors is essential to the availability and activity of these GFs (Peschon et al, 1998;Iwamoto et al, 2003;Yamazaki et al, 2003). Several members of ADAM family, including ADAM 9, 10, 12, and 17, have been implicated in the shedding of HB-EGF and AR precursors (Black et al, 1997;Blobel, 2000;Herren 2002;Sunnarborg et al, 2002;Gschwind et al, 2003;Lee et al, 2003).…”

Section: Adamts-1 May Mediate the Shedding Of Heparin-binding Egf Fammentioning

confidence: 99%

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

2005

Oncogene

150

157

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The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH 2 -and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH 2 -terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.

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“…It has been clearly shown that ADAM17 can cleave Notch1 in vitro (Brou et al, 2000). Although the physiological relevance of this cleavage activity in vivo has been challenged by the fact that Notch1 but not Adam17 (Peschon et al, 1998) is essential for embryogenesis, these genetic studies did not rule out the possibility that Adam17 and Adam10 may functionally compensate each other in activating Notch1. Our study showed that Adam17 is expressed in the embryonic heart tissues.…”

Section: Discussionmentioning

confidence: 99%

Adam10 is essential for early embryonic cardiovascular development

Zhang

Tian

Chi

et al. 2010

Developmental Dynamics

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Notch pathway has been demonstrated to regulate cardiovascular development. One important step in Notch pathway is the cleavage of Notch receptor, during which an intracellular fragment of Notch protein is released to activate downstream genes. It is still uncertain whether Adam10, the mammalian homologue of Kuzbanian in Drosophila, is required to activate the Notch pathway during cardiovascular development. To further understand the physiological function of Adam10 in vascular and cardiac development, we generated mice lacking the Adam10 gene primarily in the endothelial compartment. We found that disruption of Adam10 in endothelial cells resulted in embryonic death after embryonic day 10.5 due to multiple cardiac and vascular defects similar to Notch1 mutants. We further showed that the expression of Notch target genes Snail and Bmp2 are impaired in Adam10‐deficient cardiac tissues. Finally, we provide experimental evidence to support that Adam10 functions in a cell autonomous manner during mammalian cardiac development. Developmental Dynamics 239:2594–2602, 2010. © 2010 Wiley‐Liss, Inc.

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An Essential Role for Ectodomain Shedding in Mammalian Development

Cited by 1,498 publications

References 38 publications

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

Adam10 is essential for early embryonic cardiovascular development

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