Membrane protein secretases

Abstract

A diverse range of membrane proteins of Type 1 or Type II topology also occur as a circulating, soluble form. These soluble forms are often derived from the membrane form by proteolysis by a group of enzymes referred to collectively as 'secretases' or 'sheddases'. The cleavage generally occurs close to the extracellular face of the membrane, releasing physiologically active protein. This secretion process also provides a mechanism for down-regulating the protein at the cell surface. Examples of such post-translational proteolysis are seen in the Alzheimer's amyloid precursor protein, the vasoregulatory enzyme angiotensin converting enzyme, transforming growth factor-alpha, the tumour necrosis factor ligand and receptor superfamilies, certain cytokine receptors, and others. Since the proteins concerned are involved in pathophysiological processes such as neurodegeneration, apoptosis, oncogenesis and inflammation, the secretases could provide novel therapeutic targets. Recent characterization of these individual secretases has revealed common features, particularly sensitivity to certain metalloprotease inhibitors and upregulation of activity by phorbol esters. It is therefore likely that a closely related family of metallosecretases controls the surface expression of multiple integral membrane proteins. Current knowledge of the various secretases are compared in this Review, and strategies for cell-free assays of such proteases are outlined as a prelude to their ultimate purification and cloning.

Selective transduction of protease-rich tumors by matrix-metalloproteinase-targeted retroviral vectors

“…14 Protease targeting may also be of value outside the cancer gene therapy field. Membrane-associated proteases have been implicated in many cellular processes including cell motility, 23 ligand shedding 24 and receptor activation 25 and many of these proteins are known to be expressed in a tissue-specific manner. Knowledge of the substrate specificity of these alternative protease targets will be of value to guide the design of novel proteaseactivatable vectors.…”

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

“…Apoptosis and activation of NF-jB are initiated by p55TNFR, whereas p75TNFR appears to play a direct role in only a limited number of TNF responses [6,9]. Several functionally diverse proteins, such as growth factors and cytokines and including TNF, are initially synthesized as biologically active membrane-anchored molecules that are subsequently released from the cell by proteolysis [10]. Thus, surface localization may serve to restrict activity to specific microenvironments, whereas release may lead to distal effects.…”

Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: Involvement of Src tyrosine kinase

“…Generation of the CTF was blocked by a zinc metalloproteinase inhibitor, indicating that DDR1 might constitute a novel target for limited proteolysis by a family of enzymes known as disintegrin metalloproteinases, or secretases [Hooper et al, 1997;Arribas and Borroto, 2002;Vogel, 2002].…”

“…Secretases cleave transmembrane proteins near the external face of the membrane, resulting in shedding of their ectodomains [Hooper et al, 1997;Arribas and Borroto, 2002], and many are members of the ADAM (a disintegrin and metalloproteinase) family. ADAM17, also known as tumor necrosis factor-α converting enzyme (TACE), catalyzes shedding of the majority of transmembrane proteins known to undergo secretory processing, although ADAM9, ADAM10, and ADAM12 also act on selected substrates in some cell lines [Schlöndorff and Blobel, 1999;Arribas and Borroto, 2002].…”