Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

“…SPC1, SPC4, and SPC6 have been localized to the trans-Golgi network and secretory granules, as well as at the cell surface and secreted to the extracellular matrix (Molloy et al, 1999;Bergeron et al, 2000;Beck et al, 2002;Tsuji et al, 2003;Nour et al, 2005). Although the effect of N-glycosylation has not yet been directly assessed on the structure of TGF␤ family proteins, experiments with synthetic peptides have demonstrated that N-linked glycans can induce a compact ␤-turn in the vicinity of the carbohydrate addition (O'Conner and Imperiali, 1998;Helenius and Aebi, 2001).…”

“…Calcium-dependent serine endoproteases of the subtilisin-like proprotein convertase family (SPCs) recognize the consensus R-X-X-R motif found in many intercellular signaling molecule proproteins, including Nodal and Lefty (Nakayama, 1997;Molloy et al, 1999). SPCs, of which there are seven distinct mammalian family members, have been shown to localize to the intracellular secretory network as well as having been detected as associated with the extracellular matrix.…”

“…SPCs, of which there are seven distinct mammalian family members, have been shown to localize to the intracellular secretory network as well as having been detected as associated with the extracellular matrix. SPCs may, therefore, work in both a cellautonomous and non-cell-autonomous manner (Nakayama, 1997;Molloy et al, 1999). SPC-mediated cleavage releases the active ligand during the maturation of TGF␤ proteins (Kingsley, 1994;Nakayama, 1997;Cui et al, 1998;Constam and Robertson, 1999;Molloy et al, 1999;Ulloa et al, 2001;Beck et al, 2002;Sakuma et al, 2002;Ben-Haim et al, 2006).…”

“…SPCs may, therefore, work in both a cellautonomous and non-cell-autonomous manner (Nakayama, 1997;Molloy et al, 1999). SPC-mediated cleavage releases the active ligand during the maturation of TGF␤ proteins (Kingsley, 1994;Nakayama, 1997;Cui et al, 1998;Constam and Robertson, 1999;Molloy et al, 1999;Ulloa et al, 2001;Beck et al, 2002;Sakuma et al, 2002;Ben-Haim et al, 2006). Although mammalian Lefty molecules have been shown to undergo proteolytic cleavage by SPC1, SPC4, and SPC6 in several transfected cell lines, the endogenous SPC enzyme(s) that is involved in proteolytic processing of Lefty in vivo is currently not known (Ulloa et al, 2001;Beck et al, 2002;Sakuma et al, 2002).…”

A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen

“…[13][14][15][16] The ubiquitous endoprotease furin is involved in the physiologic conversion of a broad spectrum of precursors into active protein compounds including several growth factors, hormones, plasma proteins, receptors, and matrix metalloproteinases. 17,18 Furthermore some constituents of pathogens, such as human immunodeficiency virus gp160 and diphtheria toxin, are processed in this manner. 18 It has been known that the endoprotease furin recognizes a consensus cleavage site of -ArgXLys/ ArgArg.…”