Designer TGFβ Superfamily Ligands with Diversified Functionality
نویسندگان
چکیده
Transforming Growth Factor--beta (TGFβ) superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs), and Bone Morphogenetic Proteins (BMPs), are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer), to engineer chemically-refoldable TGFβ superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-βA and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGFβ superfamily ligands through development of novel chimeric TGFβ ligands with diverse biological and clinical values.
منابع مشابه
چندشکلی واریانت های G1 و B4 ژنهای GDF9 و BMP15 در گوسفند دالاق
Recently, mutations with major influence on ovulation rate and litter size were identified in TGFβ superfamily ligands and receptors. This study was conducted to identify polymorphisms in GDF9 and BMP15 genes in Dalagh sheep breed. One hundred mature ewes from two flocks in Golestan province were genotyped for the GDF9 (G1) and BMP15 (B4) variants. Two fragments of 462bp and 153bp of GDF9 and B...
متن کاملIntracellular signaling: Fleshing out the TGFβ pathway
Members of the transforming growth factor β (TGFβ) family of signalling molecules are found in a wide variety of, and perhaps all, multicellular animals and are involved in many essential developmental processes. Not surprisingly, some member of the superfamily has been found to be present in most tissues that have been examined. In the last few years, most of the effort in the study of how TGF...
متن کاملIntertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion
In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and acti...
متن کاملXenopus Mad Proteins Transduce Distinct Subsets of Signals for the TGFβ Superfamily
Xenopus cDNAs homologous to the Drosophila Mad gene and C. elegans CEM genes have been cloned and functionally analyzed by microinjection into frog embryos. The results show that these genes (Xmad) encode intracellular proteins that act downstream of TGF beta superfamily ligands. Most interesting is the fact that different Xmad proteins produce distinct biological responses. Xmad1 produces vent...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 6 شماره
صفحات -
تاریخ انتشار 2011