a | Furin-mediated cleavage of pro-β-nerve growth factor (NGF) produces the 13-kDa β-NGF neurotrophin that binds to Trk receptors to promote synaptic innervation. Sorting nexin-15 (SNX-15), a PX-domain containing protein that binds phosphoinositides, modulates furin sorting through endosomes.įurin in development, homeostasis and disease. On the basis of the similar itinery of carboxypeptidase D (CPD), movement of furin from a post-TGN endosomal compartment to the cell surface might also require PP2A (dashed lines).

Hence, the TGN- and peripheral-cycling loops are essentially mirror images of each other. By contrast, CK2-phosphorylated furin is recycled back to the plasma membrane in a PACS-1-dependent step. Once inside early endosomes, furin molecules that are dephosphorylated by specific protein phosphatase 2A (PP2A) isoforms are delivered to the TGN, apparently through a late endosomal compartment.

The dynamin/clathrin-dependent internalization of cell-surface furin is mediated principally by the tyrosine-based motif, which binds to AP-2. Furin molecules arriving at the cell surface can be tethered by the cytoskeletal protein filamin, which is also called actin-binding protein (ABP)-280. Phosphofurin acidic cluster sorting protein-1 (PACS-1) connects the casein kinase 2 (CK2)-phosphorylated furin acidic cluster to AP-1/clathrin to retrieve furin to the TGN either from ISGs, prior to their progression to mature secretory granules (MSGs), or from endosomes. In endocrine and neuroendocrine cells, AP-1 directs furin budding from the TGN into immature secretory granules (ISGs). Budding of furin from the trans-Golgi network (TGN) is mediated by the binding of the tyrosine-based or di-leucine-like hydrophobic sorting motifs to adaptor protein (AP)-1, which targets furin to endosomes, or binding to AP-4, which targets furin to the basolateral surface from either the TGN or possibly endosomes. © (2002) American Society for Biochemistry and Molecular Biology. The Arg75 cleavage is followed by the rapid dissociation of the propeptide fragments and disinhibition of furin. Following propeptide excision, the inactive propeptide complex transits to late secretory compartments - trans-Golgi network (TGN)/endosomes - where the relatively acidic pH promotes autoproteolytic, intramolecular cleavage of the propeptide at a second, internal site (Arg75). These data indicate that both the ER and ERGIC compartments participate in the initial steps of furin activation. Propeptide excision can be blocked by inactivating furin and results in the accumulation of an apparent folding intermediate in the ER–Golgi intermediate compartment (ERGIC)/ cis-Golgi network. The propeptide, however, remains associated with the mature domain and functions as a potent autoinhibitor in trans during transport to the late secretory pathway.

After the initial endoplasmic reticulum (ER) folding events, furin undergoes autoproteolytic intramolecular excision of the propeptide at Arg107. Following translocation and signal sequence removal, the furin prodomain acts as an intramolecular chaperone (IMC) to facilitate folding of the unstructured, inactive catalytic domain (pink circle) into the active conformation (red oval). Fly is a skills laboratory that is a by-product of the history and experience of the Forgital Group.īorn of the entrepreneurial aptitude of a family that has been working in metals since the second half of the 19th century, Forgital today is the brand that represents the most modern and specialised technologies in the fabrication of rolled rings without welding in steel, nickel alloys, aluminium, titanium, and copper, used by all the sectors of the machining industry, especially in the Oil&Gas, Transmission, Power Generation, General Mechanics, and Aerospace markets.įly perfectly integrates the Forgital CSC™, the efficient Compact Supply Chain System of the Forgital Group, which enables the various members of the Group to operate as a system to supply the client with a complete service that encompasses everything from concurrent engineering of forged pieces to the assembly of the finished products.įly also integrates the possibility of coordinated measuring during the phases both before and after machining and, when necessary, provide useful feedback for the engineering phase of the forging.The furin autoactivation pathway.

Cutting edge