Shedding of XXXX ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase.

@entity8111 @entity556 @entity32138 @entity13221 @entity669 @entity597
The @entity13221 family of four transmembrane heparan @entity597 proteoglycans binds a variety of soluble and insoluble extracellular effectors. @entity13221 extracellular domains (ectodomains) can be shed intact by proteolytic cleavage of their core proteins, yielding soluble proteoglycans that retain the binding properties of their cell surface precursors. Shedding is accelerated by PMA activation of protein kinase C, and by ligand activation of the @entity556 (G-protein-coupled) and EGF (protein @entity669 kinase) receptors (Subramanian, S.V., M.L. Fitzgerald, and M. Bernfield. 1997. J. Biol. Chem. 272:14713-14720). @entity32138 ectodomains are found in acute dermal wound fluids, where they regulate growth factor activity (Kato, M., H. Wang, V. Kainulainen, M.L. Fitzgerald, S. Ledbetter, D.M. Ornitz, and M. Bernfield. 1998. Nat. Med. 4:691-697) and proteolytic balance (Kainulainen, V., H. Wang, C. Schick, and M. Bernfield. 1998. J. Biol. Chem. 273:11563-11569). However, little is known about how @entity13221 ectodomain shedding is regulated. To elucidate the mechanisms that regulate @entity13221 shedding, we analyzed several features of the process that sheds the @entity32138 ectodomains. We find that shedding accelerated by various physiologic agents involves activation of distinct intracellular signaling pathways; and the proteolytic activity responsible for cleavage of @entity13221 core proteins, which is associated with the cell surface, can act on unstimulated adjacent cells, and is specifically inhibited by @entity8111 inhibitor. In addition, we find that the @entity13221 core protein is cleaved on the cell surface at a juxtamembrane site; and the proteolytic activity responsible for accelerated shedding differs from that involved in constitutive shedding of the @entity13221 ectodomains. These results demonstrate the existence of highly regulated mechanisms that can rapidly convert syndecans from cell surface receptors or coreceptors to soluble heparan @entity597 proteoglycan effectors. Because the shed ectodomains are found and function in vivo, regulation of @entity13221 ectodomain shedding by physiological mediators indicates that shedding is a response to specific developmental and pathophysiological cues.
