Inhibitor of apoptosis (IAP) proteins are a family comprised of a total of eight mammalian members that were initially described to act as endogenous inhibitors of caspases. In addition, extensive evidence has been accumulated over the last years showing that IAP proteins can regulate various signal transduction pathways, thereby exerting non-apoptotic functions beyond the inhibition of apoptosis. For example, IAP proteins have been implied in the control of cell motility, migration, invasion and metastasis. However, currently the question is controversially discussed whether or not they positively or negatively control these processes. As small-molecule inhibitors of IAP proteins have entered the stage of clinical evaluation as experimental cancer therapeutics, a better understanding of their various cellular effects will be critical for their rational use in the treatment of human diseases.
Inhibitor of apoptosis (IAP) proteins are a family of proteins that are involved in the regulation of various signaling pathways. Although they were initially described to function as endogenous inhibitors of caspases,1 it has become increasingly clear that IAP proteins exert additional functions besides the negative regulation of apoptosis. Indeed, IAP proteins have been implicated in the control of several non-apoptotic events, including differentiation, cell motility, migration, invasion and metastasis.
Aberrantly high expression of IAP proteins is a hallmark of various human cancers and has been linked to tumor progression, treatment failure and poor prognosis. Since these data indicate that IAP proteins represent relevant therapeutic targets in cancer cells, various drug development efforts made over the last decade aimed at neutralizing the anti-apoptotic function of this family of proteins. Some of these strategies have entered the clinical stage and are currently under evaluation in clinical trials. In light of the various cellular functions of IAP proteins, it is therefore a timely and relevant endeavor to discuss some non-apoptotic activities of IAP proteins that might also be affected by small-molecule IAP antagonists.
IAP protein family
Historically, the first members of the IAP family, that is, baculovirus-encoded Op-IAP and Cp-IAP genes, were discovered using a genetic complementation assay.2, 3 In humans, eight members of the IAP protein family are currently known, including neuronal apoptosis inhibitory protein, cellular IAP1 (cIAP1), cellular IAP2 (cIAP2), X chromosome-linked IAP (XIAP), survivin, baculovirus IAP repeat (BIR)-containing ubiquitin-conjugating enzyme (BRUCE/Apollon), melanoma-IAP (ML-IAP), and IAP-like protein 2 (reviewed in Salvesen and Duckett4 and Ndubaku et al.5). The five IAP proteins that have been implicated in the regulation of migration, invasion and metastasis are displayed in Figure 1.
Structure of IAP proteins
IAP proteins are composed of several functional domains. The signature BIR domain, a 70–80 amino-acid zinc-binding domain that is conserved across species, represents the characteristic trait of all IAP proteins. Although two IAP proteins, that is, ML-IAP and survivin, contain only one copy of this motif, most IAP proteins comprise up to three BIR domains. Various types of protein–protein interactions between IAP proteins on one side and the respective interaction partners on the other side are mediated via the BIR domains. For example, BIR domains are required for the inhibition of caspase activity by XIAP. Structural studies revealed that XIAP inhibits caspase-9 via binding of its BIR3 domain to the N-terminus of the small subunit of processed caspase-9, which contains a sequence that is homologous to the four amino-acid IAP-binding motifs in Smac.6, 7 By comparison, the BIR1 and BIR2 domains of XIAP have been shown to be required for the inhibition of caspases-3 and -7.8, 9, 10, 11 Furthermore, XIAP ubiquitin-ligase activity has been shown to be required for inhibition of caspases in vivo.12
In addition to the BIR domain, several IAP proteins, including XIAP, cIAP1, cIAP2 and ML-IAP harbor a really interesting new gene (RING) domain at their carboxy terminus.1 This domain contains E3 ubiquitin ligase activity and is defined by a catalytic zinc-finger-like module that coordinates two zinc ions.13, 14 The ubiquitin E3 ligase activity of IAP proteins allows them to regulate the protein stability of many cell death modulators and effectors including caspases and IAP proteins themselves with direct consequence on cellular survival (reviewed in Vucic et al.15). Of note, IAP proteins can conjugate several types of ubiquitin chains including K11-, K48- and K63-linked chains that serve not only as tags to target proteins for proteasomal degradation, but also as signaling modules.14 Recently, IAP antagonists have been shown to induce a conformational change in cIAP1 protein that promotes E3 ligase activation via dimerization.16 In the absence of an endogenous ligand or small-molecule antagonist, multidomain cIAP1 sequesters the RING domain, thereby preventing RING dimerization.16 Binding of small-molecule antagonists to BIR domains of cIAP1 triggers conformational changes that lead to RING dimerization and increased E3 ligase activity.16 Some IAP proteins comprise additional protein motifs, for example, the caspase recruitment domain of cIAP proteins, which was suggested to serve as an autoinhibitory domain that prevents the activation of cIAP1’s E3 activity by inhibiting the dimerization of the RING domain.17 Additional functional motifs of IAP proteins include the ubiquitin-associated domain that can bind to mono- or polyubiquitin chains,18, 19 the ubiquitin-conjugating domain of apollon/BRUCE, the coiled-coil region of survivin, and the nucleotide-binding and oligomerization domain as well as the leucine-rich repeat domains of neuronal apoptosis inhibitory protein.20, 21, 22, 23, 24
Functions of IAP proteins
Regulation of cell death programs by IAP proteins has extensively been studied and is the subject of several recent reviews.1 It is worthwhile to note that in contrast to XIAP, other IAP proteins did not turn out to function as potent inhibitors of caspases,25, 26 further supporting the notion that IAP proteins may exert additional functions besides caspase inhibition. As the current review focuses on the non-apoptotic functions of IAP proteins, their impact on signal transduction pathways beyond cell death will primarily be discussed.
IAP proteins, in particular cIAP proteins, have an important role in the regulation of nuclear factor-κB (NF-κB) signaling (Figure 2). The transcription factor NF-κB comprises five members whose homo- and heterodimers positively or negatively control the transcription of a large variety of NF-κB-responsive genes that in turn mediate distinct biological effects (reviewed in Scheidereit27). For example, NF-κB-stimulated transactivation of anti-apoptotic genes such as XIAP, Bcl-2 or Bcl-XL antagonizes apoptosis, whereas upregulation of pro-inflammatory or migratory genes, for example, tumor necrosis factor (TNF)α or interleukin-8, may promote inflammation or migration. Among the upstream signaling pathways that trigger transactivation of NF-κB-regulated genes, the canonical (classical) and the non-canonical (alternative) signaling pathways have been studied most extensively.
In the canonical pathway, NF-κB proteins are held in check in the cytoplasm under resting conditions by inhibitor of κB (IκB) proteins. On ligation of TNF receptor by TNFα, activated TNF receptor serves as a platform for the recruitment of adaptor and signaling molecules such as TNF receptor type 1-associated death domain protein, receptor-interacting protein, TNF receptor-associated factor, cIAP1 and cIAP2.28, 29, 30, 31, 32 This results in cIAP-dependent non-degradative ubiquitination of receptor-interacting protein 1, recruitment of TGFβ-activated kinase (TAK)1/TAK1-binding protein kinase complex, NF-κB essential modulator, inhibitor of nuclear factor κB kinase (IKK) (IκB kinase) complex and linear ubiquitin complex, activation of IKKβ and, subsequently, phosphorylation and proteasomal degradation of IκBα (reviewed in Scheidereit27). This liberates NF-κB proteins to translocate from the cytosol into the nucleus to stimulate transcription of NF-κB target genes.
Compared with this positive regulation of canonical NF-κB signaling by cIAP proteins, signaling via the non-canonical NF-κB pathway is typically suppressed by cIAP proteins (Figure 3), as they constitutively trigger ubiquitination and proteasomal degradation of NF-κB-inducing kinase (NIK) via a cytoplasmic multi-protein complex composed of cIAP proteins, TNF receptor-associated factor 2 and 3.33, 34, 35, 36, 37, 38, 39 Ligand-mediated activation of the non-canonical NF-κB pathway leads to cIAP protein-dependent autoubiquitination and their degradation,15, 16, 40, 41, 42 which allows NIK accumulation, NIK-mediated activation of IKKα43, 44 and proteasomal processing of the p100 precursor protein to the p52 NF-κB subunit that translocates into the nucleus for transcriptional activation of NF-κB target genes (reviewed in Dejardin45).
In addition to regulating the NF-κB cascade, IAP proteins have also been implicated in the control of the mitogen-activated protein kinase (MAPK) pathway. Recently, it has been shown that cIAP proteins are necessary for the activation of MAPK signaling in response to stimulation of several ligands of the TNF receptor superfamily, including TNFα, TL1A, TWEAK or CD40 ligand.46 Furthermore, XIAP has been implied to modulate signal transduction by TGF-β and bone morphogenetic protein signaling, mainly through its ability to bind the kinase complex of TAK1 and TAK1-binding protein 1 through its BIR1 domain, Jun N-terminal kinase or phosphatidylinositol 3 kinase/Akt.47, 48, 49, 50, 51
In addition, IAP proteins have been implicated in the control of innate and adaptive immunity, for example via their ability to regulate the ubiquitination of receptor-interacting protein 2 and nucleotide-binding oligomerization domain signaling,52, 53, 54 Toll-like receptor signaling,55 nucleotide-binding oligomerization domain-like receptor signaling56, 57 and retinoic-acid-inducible gene-1 signaling.58 As a comprehensive review on the involvement of IAP proteins in the control of immune signaling is beyond the scope of this review, the readers are referred to recent excellent overviews on this topic.59, 60
In vivo, inactivation of the ubiquitin-ligase activity of XIAP by gene targeting of its RING motif revealed a role of XIAP in the regulation of tumor growth.12 Along the same lines, inhibition of the endogenous XIAP antagonist Sept4/ARTS was reported to enhance tumor formation in a genetic mouse model in vivo.61
Regulation of migration, invasion and metastasis by IAP proteins
Over the last years extensive evidence has been accumulated showing that IAP proteins are involved in the regulation of migration, invasion and metastasis (Figure 4). Interestingly, the role of IAP proteins in cell motility may even be evolutionary conserved, because overexpression of the Drosophila inhibitor of apoptosis 1, one of the IAP homologs in Drosophila, has been described to rescue migration defects caused by a dominant-negative form of the GTPase Rac.62 IAP-mediated regulation of non-lethal caspase functions might also be involved in this process, as modulation of Dronc activity also affected cell migration.62 As caspases have been shown to have non-apoptotic functions, including the regulation of cell motility and migration,63 IAP proteins may modulate migration by altering caspase activity.
On one hand, several studies support a model according to which IAP proteins promote migration, invasion and metastasis. For example, XIAP has been reported to increase cell motility of cancer cells by directly interacting with the Rho GDP dissociation inhibitor (RhoGDI) via its RING domain.64, 65 This in turn results in reduced RhoGDI SUMOylation, decreased RhoGDI activity, increased recruitment of ARP2/3 to the cytoskeleton, enhanced polymerization of actin and increased cell motility.66 Accordingly, XIAP knockdown or knockout cells exhibited a marked reduction in β-actin polymerization and cytoskeleton formation associated with decreased cell migration and invasion.66 Vice versa, reconstitution of XIAP expression in XIAP-deficient cells restored the XIAP-mediated negative regulation of RhoGDI SUMOylation and activity, leading to an increase in cell motility and cell migration.66 Notably, these effects of XIAP on cell motility occurred independently of its ability to regulate caspase activation.66 Subsequently, the structural basis of the XIAP-mediated regulation of cancer cell migration was systematically investigated in XIAP-deficient colon carcinoma cells that were reconstituted with distinct XIAP domains.64 Re-expression of full-length XIAP or XIAP lacking the BIR domains was able to rescue β-actin expression, actin polymerization and cancer cell motility.64 In contrast, XIAP missing the RING domain or XIAP H467A mutant without E3 ligase activity failed to compensate the defect in cell migration because of XIAP deficiency.64 Although the RING domain was shown to interact with RhoGDI independently of its E3 ligase activity,64 these data demonstrate that the E3 ligase activity of XIAP RING domain has an important role in the control of cancer cell motility.
Also, XIAP was reported to modulate the activities of Raf-1, focal adhesion kinase (FAK) and FAK-related nonkinase, the autonomously expressed C-terminal domain of FAK67, 68, 69 and to stabilize the α(5)-integrin-associated focal adhesion complex,70 thereby regulating cell motility, adhesion and migration. XIAP is recruited into the α(5)-integrin complex via caveolin-1 binding and mediates the efficient recruitment of FAK into the α(5)-integrin-caveolin-1-XIAP–FAK multicomplex.70 High expression levels of XIAP have also been implicated in a metastasis-enabling anoikis-resistance phenotype in cancers.71
Further, a heteromeric, cytosolic complex containing both XIAP together with survivin was shown to be required for promoting cancer cell invasion and eventually metastasis.72 Of note, these XIAP and survivin-stimulated effects occurred independently of the negative regulation of cell death by IAP proteins, but critically relied on their ability to engage NF-κB signaling.72 Accordingly, the formation of the intermolecular XIAP/survivin complex was shown to be required for the activation of the canonical NF-κB cascade.72 The BIR1 domain of XIAP has previously been described to directly interact with TAK1-binding protein 1, an upstream adaptor for the activation of the kinase TAK1, which in turn couples to the IKK complex.48 The resulting increase in IKK activity then promotes IκBα phosphorylation followed by its degradation, nuclear translocation of the NF-κB subunit p65, increased binding of NF-κB complexes to DNA and transcriptional activation of NF-κB target genes. The XIAP/survivin complex was found to upregulate the NF-κB target gene fibronectin by several hundred folds.72 This NF-κB-mediated increase in fibronectin expression promoted signaling via β1 integrins in an autocrine/paracrine fashion, resulting in increased activation of cell motility kinases such as FAK and Src.72 Eventually, engagement of these signaling events facilitated cancer cell invasion in vitro, suppressed anoikis and enhanced dissemination of tumor cells to distant organs in vivo.72 Besides fibronectin, additional β1 integrin ligands may also be involved in mediating the XIAP/survivin-triggered increase in cell migration and invasion, as neutralization of fibronectin was found to partially, but not completely block these IAP protein-mediated effects.72 Although the increased NF-κB activity in response to the XIAP/survivin heteromer contributed to upregulation of a broad signature of genes involved in cancer cell adhesion such as fibronectin,72 this IAP protein-mediated NF-κB activation did not result in morphological features of epithelial–mesenchymal transition, as no alterations in expression levels of E-cadherin, matrix metalloproteinase-2 or -9 were detected.72 By comparison, NF-κB has previously been shown to promote metastasis of tumor cells by stimulating epithelial–mesenchymal transition.73
In another study, the caspase recruitment domain of cIAP1 was shown to suppress activation of its E3 activity by preventing RING dimerization, while deregulated activation of cIAP1 led to enhanced cell proliferation and migration.17 Furthermore, targeting of IAP proteins, for example, by a Smac mimetic, was shown to interfere with the enhanced invasion and metastasis of cholangiocarcinoma cells on administration of TRAIL.74
On the other hand, a number of studies support the concept that IAP proteins suppress migration and invasion. Accordingly, several IAP proteins, including XIAP, cIAP proteins and ML-IAP, were reported to regulate the turnover of Ras family proteins including C-rapidly accelerated fibrosarcoma (C-RAF) and Ras-related C3 botulinum toxin substrate (Rac)1, thereby modulating the MAPK signaling pathway and cell migration.75, 76, 77 C-RAF belongs to the Ras effector proteins as part of the MAPK cascade and is involved in the control of various biological functions, including migration and invasion.78 XIAP and cIAP proteins were demonstrated to directly bind to C-RAF and to initiate ubiquitylation of C-RAF in an Hsp90/C terminus of Hsc70-interacting protein (CHIP)-mediated manner.75 Interestingly, protein degradation of C-RAF depended on CHIP, a chaperone-associated ubiquitin ligase, whereas it occurred independently of the E3 ligase activity of IAP proteins.75 Binding of XIAP led to a conformational change of C-RAF, which facilitated the interaction of CHIP with the C-RAF-Hsp90 complex and proteasomal degradation of C-RAF by CHIP.75 Small interfering RNA-mediated silencing of XIAP or cIAP proteins resulted in stabilization of C-RAF and increased cell migration in a C-RAF-dependent manner.75 Similarly, ML-IAP, an IAP family member that contains a single BIR domain, was found to directly bind to C-RAF, targeting it for proteasomal degradation.77 In addition, ML-IAP directly interacts with XIAP and can regulate C-RAF stability in a heteromeric complex together with XIAP.77 Vice versa, loss of ML-IAP was shown to result in increased MAPK activity and cell migration.77
Rac1 belongs to the Ras family of small GTPases that is ubiquitously expressed and controls numerous basic cellular processes such as actin cytoskeleton remodeling and cell migration.79 Although the activity of Rho GTPases is well known to be under the control of guanine-nucleotide exchange factor and GTPase-activating proteins,79 recent evidence demonstrates that post-translational modifications such as ubiquitination represent an additional mechanism to modulate Rho GTPase activity.76 XIAP and cIAP1 were shown to interact with Rac1, thereby facilitating the conjugation of polyubiquitin chains to Rac1 and targeting it for degradation via the proteasome.76 Interestingly, XIAP and cIAP1 can directly bind to Rac1 in a nucleotide-independent manner,76 pointing to a regulatory mechanism that is distinct from the regulation of Rho GTPases by guanine-nucleotide exchange factor and GTPase-activating proteins. Consistently, downregulation of XIAP or cIAP1 by pharmacological or genetic tools resulted in reduced proteasomal degradation of Rac1, elevated Rac1 protein levels and an increase in cell motility and migration associated with an elongated morphology.76 In addition to regulating cancer cell migration, IAP proteins were also demonstrated to promote the migration of non-malignant cells in a zebrafish model, that is, of neuronal progenitor cells in the developing central nervous system.76
What are the possible explanations for these controversial reports on the control of migration, invasion and metastasis by IAP proteins? The balance in proliferation and cell death that is under the control of IAP proteins may account for some differences between the studies, as IAP proteins are key repressors of apoptosis. As loss of cIAP1/2 was previously reported to reduce the proliferation rate,17 changes in proliferation may have an impact on cancer cell migration. Furthermore, the experimental approach to antagonize IAP proteins in cancer cells, that is, using genetic manipulation or pharmacological tools, may affect the final outcome, as IAP proteins regulate signal transduction pathways via various mechanisms, including their enzymatic E3 ligase activity or protein-protein interactions. Also, context-dependent factors, including differences in cell types (for example, malignant/non-malignant, mammalian/murine) might influence the way in which inhibition of IAP proteins will affect cell migration and invasion. In addition, constitutive expression levels of individual IAP proteins in a given cell as well as distinct pharmacodynamics properties of different Smac mimetics may contribute to differences in cellular responses. Furthermore, IAP proteins may modulate cellular signaling pathways in a non-autonomous manner, as suggested by recent evidence showing that apoptotic cells may mediate mitogenic signaling and stimulate proliferation of surrounding cells.80
In addition to regulate cell death signaling pathways and in particular apoptosis, IAP proteins can also exert several non-apoptotic functions, including the control of migration, invasion and metastasis. The question whether or not IAP proteins positively or negatively modulate these processes has controversially been discussed, suggesting that the impact of IAP proteins on migration, invasion and metastasis may be, at least to a large extent, context-dependent. Also, little is known about whether the different types of ubiquitin chains that are conjugated by IAP proteins may contribute to these differences, as they may exert signaling functions besides flagging their targets for proteasomal degradation. In addition, the discovery of additional proteins that are subject to IAP protein-mediated ubiquitin modifications will likely shed more light on the factors that govern the regulation of cell motility and invasion by IAP proteins. As small-molecule pharmacological antagonists of IAP proteins are currently undergoing evaluation in early clinical trials, a better understanding of the non-apoptotic functions of IAP proteins will be critical to avoid unwanted side effects of therapeutic IAP inhibition. Therefore, further studies on the biological processes that are under the control of IAP proteins are clearly warranted.
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The expert secretarial assistance of C Hugenberg is greatly appreciated. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, the Ministerium für Bildung und Forschung (01GM0871, 01GM1104C), European Community and Jose Carreras Stiftung.
The author declares no conflict of interest.
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Fulda, S. Regulation of cell migration, invasion and metastasis by IAP proteins and their antagonists. Oncogene 33, 671–676 (2014). https://doi.org/10.1038/onc.2013.63
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