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Transforming the Cell Surface Through Proteolysis Laura L Kiessling and Eva J Gordon

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Transforming the Cell Surface Through Proteolysis Laura L Kiessling and Eva J Gordon Review R49 Transforming the cell surface through proteolysis Laura L Kiessling and Eva J Gordon Protein shedding, or the proteolytic cleavage of a protein from Introduction the surface of a cell, is emerging as an important mechanism in Cells have the remarkable ability to direct the functions the regulation of cellular activity but it is poorly understood. and activities of their thousands of proteins through Growing evidence suggesting that protein shedding and several mechanisms. One of these is phosphorylation - a protein function are closely linked may lead to new strategies reversible modification that affects function by changing for the treatment of a wide range of diseases. protein-protein interaction propensities. An alternative and more permanent way to direct cellular processes is by Address: Departments of Chemistry and Biochemistry, University of proteolysis. Intracellularly, proteolysis can regulate the Wisconsin-Madison, Madison, WI 53706, USA. presence of specific proteins, influencing fundamental Correspondence: Laura L Kiessling processes such as the cell cycle or apoptosis, and proteoly- E-mail: [email protected] sis regulates important processes outside the cell, such as Chemistry 81 Biology March 1998,5:R49-R62 cell migration and wound repair. Proteolysis can also func- http://biomednet.com/elecref/10745521005R0049 tion as a control mechanism on the cell surface. For example, the G-protein-coupled thrombin receptor can be 0 Current BioioQy Ltd ISSN 1074-5521 activated by limited proteolysis [l]: thrombin cuts the amino terminus of its receptor, causing a conformational change that activates the receptor. Thus, regulated prote- olysis has an important role on the cell surface. This review focuses on the importance of proteolysis in the release of the extracellular portion of a protein by cleavage at the cell surface, referred to here as protein shedding. The term protein shedding has been used to describe the loss of molecules from the cell surface either through enzy- matic cleavage by proteases or lipases, or by exocytosis in membrane-derived vesicles. Here, however, protein shed- ding will be used exclusively to describe the proteolytic cleavage of proteins from the surface of the cell. A number of different cell types shed proteins from their cell surface and the proteins released are also diverse, including cytokines and cytokine receptors, growth factors and growth factor receptors, cell-adhesion molecules, Fc receptors, and G-protein-coupled receptors (Table 1). These proteins have a wide range of functions, and there is a growing interest in exploring the relationship between protein shedding and protein function. Recent reviews have provided excellent discussions about the characteristics of the enzymes involved in proteolytic release, the cleavage of leukocyte membrane molecules, and the generation and function of soluble cytokine recep- tors and growth factors [Z-6]. Here, we focus on the events that liberate the ectodomain of a transmembrane protein (Figure 1 and Table l), which we have classified into four main categories. The first group is comprised of the shed- ding processes induced by cellular activators, the second group consists of shedding processes that appear to be con- stitutive, the third comprises proteolytic cleavage events mediated by antibodies, and we also discuss emerging evi- dence suggesting that some receptors are proteolyticahy R50 Chemistry & Biology 1998, Vol5 No 3 Table 1 Proteins that are shed from the cell surface. Shedding method Proteins released Cell adhesion Cytokines/ Growth factors/ G-protein coupled molecules cytokine receptors growth factor receptors receptors Miscellaneous Activation CD43*+, CD44*5, TNFa*, TNFR-l*H$ proTGFcc*S, CSF-1 R*, TSHR CD1 4*#, CD1 6-l* CD62L*+, CD23* TNFR-II**,IL-1 RII*, HGFR*, c-kit receptor*§, CD1 6-ll*,CD30*, IL-4R*, IL-6R*# TrkA neurotrophin receptor* Fas’, LAR*, ACE*, pAPP*, class I MHC’, syndecan* Antibody1 .CD43 (antiCD43), CD1 4 (anti-CD1 4) CD44 (antXD44, anti-CDSS), CD62L (anti-CDBPL, anti-Leu-13, anti CD45, anti-CD1 6, anti-CD95), CD23 (antiCD20) LigandY CD62L (neoglycopolymer), IL-3R (IL-3), TrkA neurotrophin TSHR (TSH), CD1 4? (LPS) CD44? (hyaluronate), TNFR-I (TNFa), receptor (NGF) V2 vasopressin receptor CD43? TNFR-II (TNFa) (photoreactive vasopressin agonist) The symbols designate those cell-surface molecules that are shed in enzyme; PAPP, P-amyloid precursor protein; TNF, tumor necrosis response to the corresponding activator. This list is not all inclusive; factor; TSH, thyrotropin; IL, interleukin; TGF, transforming growth each molecule has not necessarily been tested with every activating factor; MHC, major histocompatibility complex; CSF, colony agent: *PMA, +fMLP, *LPS, %a !z+ ionophores, #toxins. IShed molecule stimulating factor; HGF, hepatocyte growth factor; NGF, nerve growth (antibody or antibodies that induce the shedding). %hed molecule factor; PMA, phorbol 1 P-myristate 13-acetate; fMLP, (ligand that induces its shedding). ACE, angiotensin converting formylmethionylleucyIphenylalanine: LPS, lipopolysaccharide. cleaved in response to ligand binding. Ligand-induced pro- cell surface conducive to adhesive interactions suggesting teolysis is a potential mechanism for regulating receptor- that CD43 shedding is an important part of the activation ligand interactions, and extends a relationship between the process [8]. Similar persuasive explanations for the func- function and regulation of receptors. tional roles of other shedding events have been suggested, but, as it is currently difficult to separate individual shed- Activation-induced shedding ding events and thus study the functional effect of shed- Cellular stimulants can induce the shedding of many pro- ding one protein at a time, it has been hard to provide teins and also cause cellular activation and concomitant rigorous tests of these explanations. changes in cell behavior. The release of protein ecto- domains appears to be one way for the cell to change the Little is known about the pathways by which cellular characteristics of its surface, eliminating activities that are stimulants induce the release of extracellular proteins. no longer necessary or are counterproductive. Although Many different agents have this capacity, including the precise relationship between the new behaviour phorbol esters, chemotactic peptides, calcium ionophorcs, adopted by the cell and the effects of protein shedding cytokines and growth factors (Figure Za). These agents all remains to be determined, there is circumstantial evidence initiate signal transduction, but use a variety of different suggesting that they are functionally linked. For example, pathways, making it difficult to identify the branch of the when leukocytes become activated they shed the leuco- pathway that triggers protein release. Most studies of acti- cyte antigen CD43 from their surface, and also become vation-promoted protein shedding have used phorbol more able to adhere to target cells. CD43 is a highly esters (such as phorbol myristate acetate [PMA]) to stimu- anionic sialomucin, proposed to function as an ‘anti-adhe- late protein kinase C (PKC) activity and some information sive’ molecule. It is found in high concentrations on circu- about how cell srimulation leads to shedding has emerged lating white blood cells, and towers over the cell surface, from these investigations. extending -45 nm beyond the membrane [7]. The nega- tive charges on CD43 are believed to prevent leukocyte Phorbol esters induce collective shedding of a wide aggregation and undesired adhesion events by both elec- variety of cell-surface molecules, resulting in the release of trostatic and sterid repulsion. When leukocytes become cytokines (e.g., TNF-a), growth factors (e.g., proTGF-a), activated, they shed CD43 from the surface, rendering the receptors (e.g., TNF receptor, IL-ZR), cell-adhesion Review Protein shedding at the cell surface Kiessling and Gordon R51 Figure 1 The liberation of the ectodomain of transmembrane proteins (protein shedding). (a) Activation-induced shedding. (b) Constitutive shedding. (c) Antibody- induced shedding. Ligandinduced (d) Activating agent shedding. + Y (b) Antigen-specific shedding Shedding of other receptors W l b Ligand Chemistry & Biology molecules (e.g., L-selectin), enzymes (e.g., angiotensin PKC. Collectively, these results suggest that PKC does converting enzyme) and proteins of unknown function not directly promote protein shedding but is perhaps an (e.g., the amyloid precursor protein) [4,9,10]. The induc- upstream modulator of these proteolytic events. tion of shedding by phorbol esters suggests that PKC may act directly to cause protein shedding. Activated PKC The sequences of protease cleavage sites for several shed phosphorylates serine and threonine residues in the cyto- proteins have been determined and they have no obvious plasmic domains of selected proteins, but for many of the similarities. When the extracellular sequences of shed shed proteins the presence of a cytoplasmic domain, and proteins are appended to proteins that are resistant to therefore a potential intracellular signaling or recognition shedding, hovvever, the resulting chimeric proteins are sus- sequence, is not required for cleavage [ll,lZ]. Addition- ceptible to proteolytic release [11,13], suggesting that pro- ally, many of the proteins released from the cell surface teins are released from the cell surface when they have using phorbol esters are not phosphorylation substrates for either
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