361 MINI-REVIEW

Metalloproteinases and the modulation of GH signaling

G Baumann and S J Frank1 Center for Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Medical School, and the Veterans Administration Chicago Health System, Lakeside Division, 303 E Chicago Avenue, Chicago, Illinois 60611, USA 1Division of Endocrinology and Metabolism, Departments of Medicine and Cell Biology, University of Alabama at Birmingham, and the Veterans Affairs Medical Center, Birmingham, Alabama 35294, USA (Requests for offprints should be addressed to G Baumann; Email: [email protected])

Abstract The metzincin metalloproteinase, tumor necrosis factor- processed by -secretase activity, possibly leading to bio- -converting enzyme (TACE), also known as ADAM (a logically active products. TACE-dependent GHR pro- disintegrin and metalloproteinase) 17, has recently been teolysis can be inhibited by GH as the dimerized GHR is identified as an important enzyme for cleavage of the GH resistant to cleavage. The cleavage site lies within a short receptor (GHR) and shedding of GH-binding juxtamembranous stem region that extends between the (GHBP). Proteolysis can be induced by phorbol esters, transmembrane helix and the globular dimerization platelet-derived growth factor and serum; it is dependent domain of the GHR. GHR proteolysis leads to down- on protein kinase C and partially on MAP kinase path- regulation of functional GHRs at the cell surface, and has ways. Proteolysis occurs at the cell surface, leading to complex secondary effects on GH action via GHBP and extracellular release of GHBP and intracellular GHR GHR remnant generation. remnant accumulation. The GHR remnant is further Journal of Endocrinology (2002) 174, 361–368

Introduction ten amino acid ‘stem’ separates the dimerization domain from the cell membrane. This stem region was not Growth hormone (GH) signals through the GH receptor visualized in the crystal. (GHR), a member of the cytokine receptor superfamily (Bazan 1989). The GHR is a 620 amino acid, integral , consisting of a 246 residue extra- The GH-binding protein (GHBP) and GHR cellular domain involved in ligand binding and GHR proteolysis dimerization, a single 24 amino acid transmembrane helix, and a 350 residue cytoplasmic domain involved in signal Many integral membrane are subjected to pro- transduction (Leung et al. 1987). The GHR signals teolytic cleavage near their membrane insertion, resulting through the Jak-Stat, MAP kinase, phosphatidylinositol in liberation of their extracellular domains into the peri- 3-kinase, and probably other pathways (Herrington & cellular space (Ehlers & Riordan 1991, Heaney & Golde Carter-Su 2001, Frank & Messina 2002). 1996, Hooper et al. 1997, Müllberg et al. 2000) – a process Binding of GH to the GHR results in ligand-induced known as ‘shedding.’ A list of integral membrane proteins GHR dimerization, with sequential binding of a first undergoing this type of proteolysis has been published in GHR to binding site 1 on GH, followed by recruitment of tabular form; it includes cell adhesion molecules, leukocyte a second GHR to site 2 (Cunningham et al. 1991). This antigens, receptors and their ligands, ectoenzymes, viral ternary complex between two GHRs and GH is then membrane proteins, and other miscellaneous proteins stabilized by direct interaction between the two GHR (Hooper et al. 1997). The GHR is a prominent member of juxtamembrane domains. Dimerization causes a conforma- this class of transmembrane proteins; it generates substan- tional change that initiates the signaling cascade. Figure 1 tial amounts of its ectodomain, known as GHBP, which shows the crystallized extracellular GHR-GH-GHR can be measured in the circulation (for review see complex (de Vos et al. 1992), with two distinct GHR Baumann 2001). The biological importance of the domains: an amino-terminal binding domain and a more GHBP, although still poorly understood, is underscored carboxy-terminal dimerization domain. An approximately by the facts that (i) it is evolutionarily conserved among

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vertebrates and (ii) it is generated by two separate mech- chelators, such as TAPI or Immunex Compound 3 (IC3), anisms: proteolytic shedding in humans, rabbits and other thereby implicating metalloproteinases of the metzincin species; and alternative GHR mRNA splicing in rodents type in the shedding process (McGeehan et al. 1994, (Baumann 2001). In rodents, a GHBP-specific exon (exon Mohler et al. 1994, Arribas et al. 1996). Similar 8A) in the GHR encodes a hydrophilic sequence in findings were subsequently reported by others (Amit et al. lieu of the hydrophobic transmembrane domain of the 2001). GHR (encoded by exon 8), thereby permitting secretion of the alternative splice product (Edens et al. 1994, Zhou et al. 1994, 1996). Even attempts to abolish alternative Metzincins, a disintegrin and metalloproteinase splicing leading to the GHBP through inactivation of the (ADAM) and TNF--converting enzyme (TACE) exon 8A splice site or its polyadenylation signal fail to deplete GHBP production, which persists via a mechan- Metzincins constitute a large family of metalloproteinases, ism of readthrough into intron 7 (Zhou et al. 1997). which are summarized in Table 1. Among the metzincins, Furthermore, the rodent GHR is not completely resistant ADAMs are especially relevant in this context as at least to proteolysis (Guan et al. 2001), a property that represents three members (ADAM 9, 10 and 17) are known plasma yet another potential mechanism to generate GHBP. membrane-resident sheddases that can be activated by Thus, GHBP production is a consistent and probably phorbol esters. ADAM 9 is involved in shedding of important feature of GH/GHR biology. This review will heparin-binding epidermal growth factor (EGF)-like focus on the proteolytic mechanism of GHBP generation, growth factor (Izumi et al. 1998). ADAM 10 (also known which operates in humans, rabbits and many other species. as Kuzbanian in the fruit fly) is a critical component of the The protease responsible for GHR cleavage/GHBP Notch pathway that is involved in Drosophila neurogenesis generation has remained a mystery for many years, but has and in human sympathoadrenal cell development (Pan & recently been identified. Rubin 1997, Yavari et al. 1998). ADAM 17 (also known as TACE) is a well-characterized protease involved in cleaving soluble TNF- as well as several other ecto- Pharmacologically induced GHBP shedding domains from their membrane-bound precursors (Black et al. 1997, Moss et al. 1997). Figure 2 depicts the domain Trivedi & Daughaday (1988) showed that sulfhydryl structure of TACE. The enzyme is synthesized as a inactivating agents, such as iodoacetamide and N-ethyl- precursor which includes a prodomain, a catalytic domain maleimide (NEM), could induce GHBP shedding from containing the Zn-binding site, a disintegrin domain, a IM-9 cells, a human lymphoblast line expressing GHR. cysteine-rich EGF/crambin domain, a transmembrane This observation led to the speculation that the domain and a cytoplasmic domain (Black et al. 1997, Moss membrane-proximate Cys241, which is unpaired, may be et al. 1997). The prodomain contains a cysteine that involved in GHR proteolysis. However, subsequent interacts with and neutralizes the Zn atom in the catalytic studies showed that substitution of Cys241 with alanine had site, thereby maintaining the enzyme in an inactive no effect on GHBP shedding (Amit et al. 1999). NEM also zymogen form during its transit through the endoplasmic has complex effects on intracellular membrane fusion and reticulum–Golgi apparatus. This prodomain is removed, protein transport through the – probably by a furin-like enzyme, before fully active TACE Golgi system (Barr et al. 1997), but it is not clear whether is displayed at the cell surface. The catalytic domain of or how this property might be linked to NEM’s effect on TACE has been crystallized, and the precise cleavage site shedding. Thus, the mechanism by which iodoacetamide in the TNF- precursor has been identified (Maskos et al. and NEM cause shedding remains poorly understood; it is 1998). Cleavage occurs in the 28 residue linear stem not considered a physiological process. region extending between the cell surface and the globular Alele et al. (1988) demonstrated that GHBP shedding TNF- domain that forms a homotrimeric structure in the could be induced by the phorbol ester phorbol 12- extracellular space (Maskos et al. 1998). Based on the myristate 13-acetate (PMA). This was accompanied by the important role of TACE as a sheddase for several cell intracellular appearance of the carboxy-terminal fragment surface proteins, we hypothesized that TACE may also of the proteolyzed GHR, the ‘GHR remnant.’ This serve as a GHBP sheddase. It is important to recognize that observation was akin to the PMA-induced ectodomain TACE has no simple specificity for a linear amino acid shedding of several other transmembrane proteins, such as sequence. For example, several well-characterized tumor necrosis factor- (TNF-), transforming growth TACE substrates show no consensus sequence for either factor- (TGF-), interleukin-6 receptor, L-selectin, and recognition or cleavage (Table 2). Moreover, the binding amyloid precursor protein, among others (Black & White affinity of TACE for synthetic cleavable peptides is rather 1998, Peschon et al. 1998a, Schlöndorff & Blobel 1999, low. For these reasons, it has been postulated that TACE Esler & Wolfe 2001). Moreover, the PMA-induced proteolysis is a complex process depending on recognition GHBP shedding could be inhibited by hydroxamate Zn of an epitope distant from the cleavage region and,

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Figure 1 Ribbon diagram of the extracellular structure of the dimerized GHR-GH complex. The outside of the cell membrane is indicated by the bubble surface at the bottom. One GHR on the left (green) and another on the right (blue) are shown together with bound GH (red). The compact ligand-binding domains as well as the dimerization domains (towards the bottom) are evident. The stem section between the cell membrane and the dimerization domain spans a linear sequence of approximately ten amino acids. Reprinted and adapted with permission from de Vos et al. 1992 (copyright 1992, American Association for the Advancement of Science; http://www.sciencemag.org). additionally, that spacial factors in the cell membrane, such GHR is pertinent. Both GHR and TACE are expressed as close apposition and proper relative orientation between ubiquitously, including in liver, an organ widely believed cognate regions of the enzyme and substrate, are required to be a major source of GHBP (Mercado et al. 1994, for efficient catalysis (Maskos et al. 1998). Maskos et al. 1998). If TACE is considered a candidate for a GHBP sheddase, the question of co-expression of TACE and the TACE as a GHBP sheddase Table 1 The metzincin family: zinc-dependent metalloproteinases Based on the hypothesis that TACE may be involved in Astacins (e.g. bone morphogenetic protein 1) GHR proteolysis, we examined cells derived from the Matrixins (e.g. collagenase) TACE knockout mouse. The TACE knockout mouse Adamalysins Snake venom metalloproteinases lacks the Zn-binding domain of TACE; it is totally devoid ADAMs (A Disintegrin And Metalloproteinase) of TACE enzymatic activity and thus represents a func- Serralysins (bacterial proteases) tional TACE null mutant (Peschon et al. 1998a). It has a www.endocrinology.org Journal of Endocrinology (2002) 174, 361–368

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Figure 2 Domain structure of TACE. The zinc active site is shown as ‘Zn’. EGF denotes the EGF-like domain, TM the transmembrane domain.

Table 2 Linear sequences proteolytically cleaved by TACE

Genbank Cleavage accession No. Reference

TNF- ...SPLAQA VRSSSR . . . M10988 Black et al. (1997) TGF- ...HADLLA VVAASQ . . . K03222 Sunnarborg et al. (2002) L-selectin . . . CQKLDK SFSMIK . . . BC020758 Peschon et al. (1998a) Interleukin-6 receptor . . . TSLPVQ DSSSVP . . . X12830 Althoff et al. (2000)

phenotype resembling the TGF- knockout or EGF considered an excellent surrogate for its physiological receptor knockout mouse, including open eyelids at birth, counterpart, diacyl-glycerol, in stimulating protein kinase stunted and aberrant hair growth, and epithelial disorgan- C (PKC) pathways. We have shown that physiological ization in multiple organs, including placenta, growth agents, such as platelet-derived growth factor (PDGF) and retardation, and pre-/perinatal mortality in 97% of animals calf serum, can also induce GHR proteolysis and GHBP (Peschon et al. 1998a). Interestingly, this phenotype does shedding (Guan et al. 2001). Furthermore, constitutive not result from deficiency of soluble TNF-, but rather GHR proteolysis is also blocked by metalloproteinase from failure to generate soluble TGF- and EGF receptor inhibitors (Alele et al. 1998, Zhang et al. 2000, 2001, Guan ligands from their membrane-bound precursors due to et al. 2001). Thus, we believe that physiological shedding lack of TACE activity. TNF- knockout mice (or TNF is mediated by the same or similar mechanisms as receptor knockout mice) have no overt phenotype unless PMA-induced shedding. challenged with infectious agents (Pasparakis et al. 1996, Marino et al. 1997, Peschon et al. 1998b), whereas TGF-- and EGF receptor-deficient mice resemble the Regulation of GHBP shedding TACE knockout mouse (Luetteke et al. 1993, Mann et al. 1993, Miettinen et al. 1995). Fibroblasts from TACE The regulation of TACE activity and GHR proteolysis is knockout mice (TACE null cells), transfected with the just beginning to be studied. Initial experiments showed highly cleavable rabbit GHR, fail to generate any detected that PKC inhibitors completely block GHBP shedding, GHBP, either basally or after exposure to PMA (Zhang whereas MEK inhibitors exert partial inhibition (Guan et al. 2000). Transfection of TACE null cells with TACE et al. 2001). These observations indicate that PKC cDNA restores their ability to generate GHBP and GHR pathways are critical for TACE activation, and that remnant, thereby strongly implicating TACE as an ERK-MAPK pathways also play a lesser role. The mech- important GHBP sheddase (Zhang et al. 2000). The fact anistic link between PKC or MAPK activation and TACE that the reconstituted shedding activity can be inhibited by activation remains to be elucidated. Whether or not native IC3 further corroborates this conclusion (Zhang et al. metalloproteinase inhibitors (TIMPs) are important in 2000). Whether other metalloproteinases may also con- regulating GHR proteolysis remains to be determined. tribute to GHBP shedding in other cell systems remains to TIMP-3 is known to bind and inhibit TACE (Amour et al. be determined. 1998). Of interest, we have found that GH itself has an We wish to emphasize that most of the experiments effect on GHR proteolysis. As indicated above, GH listed above have been performed with pharmacological binding to the GHR induces GHR dimerization, and the agents (PMA, etc.) and relatively little is known about dimerized GHR is much more resistant to proteolysis than the dynamics of constitutive GHR proteolysis. PMA is the monomeric GHR (Zhang et al. 2001). Thus, GH

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Figure 3 Proteolysis of the GHR by TACE and -secretase. The membrane-bound TACE is activated by PKC- and MAPK-dependent signals and cleaves an adjacent GHR in its juxtamembranous stem region. This liberates GHBP into the pericellular space. The GHR remnant is further cleaved by a -secretase, releasing a carboxy-terminal ‘stub’ whose fate is presently unknown. In analogy with Notch and amyloid precursor protein, which are processed by a similar mechanism to bioactive products (transcription factors), it is possible that the GHR stub also has bioactivity of its own, although this remains to be determined.

exerts a negative effect on GHR cleavage/GHBP transcription factors) remains to be determined. This is shedding by promoting GHR dimerization. an intriguing possibility that has a precedent in Notch Figure 3 summarizes the GHR cleavage events as signaling (Brou et al. 2000). presently understood. TACE, activated through PKC- and As mentioned above, there is no known linear MAPK-dependent mechanisms, cleaves the (monomeric) consensus sequence for TACE recognition or cleavage. GHR in the stem region at a presently unknown site This is also true for the GHR as a substrate. Some GHRs (preliminary experiments have identified a murine GHR (e.g. rabbit, human) are highly sensitive to proteolytic cleavage site nine residues amino-terminal to the first shedding of GHBP, whereas others (e.g. mouse, rat) are intramembranous amino acid (Wang et al. 2002)). This very resistant. There is an about 70-fold difference be- generates the soluble GHBP and a GHR remnant con- tween rabbit and mouse GHRs with respect to the sisting of the transmembrane and intracellular domains. amounts of GHBP generated in response to PMA (Guan et The GHBP is free to diffuse into the pericellular space and al. 2001). Indeed, in rodents in vivo, most if not all of the ultimately reaches the circulation. The fate of the remnant circulating GHBP is thought to be derived from alterna- is as yet incompletely understood. However, very recent tive mRNA splicing rather than proteolysis (Sadeghi et al. experiments have shown that the GHR remnant under- 1990). Comparison of the amino acid sequences in the goes another, likely intramembranous, cleavage by a juxtamembrane stem reveals no clues for this difference. -secretase-like enzymatic activity (Cowan et al. 2002), The structural requirements for GHR cleavability are akin to the presenilin cleavage of the amyloid precursor poorly understood. Of interest, a recent study reported that protein implicated in Alzheimer’s disease (Esler & Wolfe the length of the extramembrane stem is critically import- 2001), or to Notch remnant processing in Drosophila ant for cleavage as shortening by three residues abolished (Fortini 2001, Selkoe 2001). Whether the processed GHR cleavability (Conte et al. 2002). This was shown to be due remnants have biological activity in their own right (e.g. as to stem length rather than sequence-specific parameters. www.endocrinology.org Journal of Endocrinology (2002) 174, 361–368

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Impact of GHR proteolysis on GH signaling Althoff K, Reddy P, Voltz N, Rose-JohnS&Müllberg J 2000 Shedding of interleukin-6 receptor and tumor necrosis factor alpha. Contribution of the stalk sequence to the cleavage pattern of Metalloproteinase activity has at least three consequences transmembrane proteins. European Journal of Biochemistry 267 for GH action. First, GHR cleavage causes loss of 2624–2631. functional GHRs from the cell surface, a process we call Amit T, Bar-Am O, Dastot F, Youdim MB, AmselemS&Hochberg ‘receptor decapitation’. This is one form of receptor Z 1999 The human growth hormone (GH) receptor and its downregulation; it has been directly demonstrated (Guan truncated isoform: sulfhydryl group inactivation in the study of receptor internalization and GH-binding protein generation. et al. 2001). Downregulation is probably important to keep Endocrinology 140 266–272. the signaling system from being overstimulated. 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