1. Introduction
Tumor suppressor genes (TSGs) function in concert with diverse parts of the cellular machinery and integrate the signaling networks in a cell [1]. TSGs act to safeguard the networks, to fine-tune signaling outputs, and to maintain tissue homeostasis. The loss of tumor suppressor activity or inactivation of a TSG is often due to genetic alterations such as a loss-of-function mutation or a deletion in the gene; alternatively, epigenetic silencing can result from methylation or histone modification in the TSG’s promoter regulatory elements [1-3]. Cells with a loss or a significant reduction of a particular tumor suppressor’s activity are prone to develop neoplasia in the tissues/organs where the TSG is expressed [1, 2].
The properties and modes of action of TSGs can be very distinct from one class to another. Most TSGs encode proteins that participate in controlling cell cycle progression, inducing apoptosis, repairing damaged DNAs, or performing other important functions [1]. TSGs can also be a source of microRNAs, a class of small hairpin RNAs that are transcribed in many cells and may act as tumor suppressors by regulating the expression of their targeted genes [4]. In this chapter, we will focus on one class of the TSGs, represented by the mitogen-inducible gene 6 (MIG-6) and Sprouty 2 (SPRY2), whose activities are crucial in regulating receptor tyrosine kinases signaling through negative feedback loops.
Receptor tyrosine kinases (RTKs) are important cellular components, and there are nearly 60 members encoded in the genome [5, 6]. They all possess a single transmembrane domain linking their extracellular ligand-binding region to the cytoplasmic region in which the catalytic kinase domain and the domain for docking of downstream signaling molecules reside. Upon binding of the ligand to its physiologic RTK partner, the receptors dimerize, resulting in autophosphorylation of key tyrosine residues in the kinase domain. This leads to a conformational change in the receptor and the recruitment of downstream signaling molecules to its docking domain or in close proximity for phosphorylation and activation. In this cellular process, the RTK plays a central role by relaying external stimuli (ligands) to internal signaling cascades such as the RAS-MAPK or PI3K-AKT pathways, translating the signal input into biological actions ranging from mitogenesis, to motility, morphogenesis, metabolism, and many others [5, 6].
RTK signaling is essential in many developmental processes and in normal physiology, and the actions of RTKs must be controlled temporally and spatially [5, 6]. Their actions are tightly regulated at several molecular levels to ensure appropriate cellular responses. Among the mechanisms that keep RTK signaling in “check and balance” are receptor endocytosis/degradation, dephosphorylation by protein tyrosine phosphatases (PTPs), and negative feedback regulation. Signal overactivity caused by inappropriate RTK activation can lead to serious pathological outcomes, particularly cancer. Thus, many RTKs such as epidermal growth factor receptor (EGFR) and the N-methyl-N’-nitroso-guanidine human osteosarcoma (MNNG HOS) transforming gene (MET) have been classified as oncogenes, because activating mutations, amplifications or other anomalies in these receptors have been identified in various human cancers, and their roles in the development and progression of tumor malignancy have been well documented [7, 8]. For example, aberrant activation of MET can result in deregulated cell proliferation, transformation, and promotion of tumor cell invasion and metastasis [8].
Unlike the rapid attenuation resulting from receptor endocytosis/degradation or PTP-mediated dephosphorylation, negative feedback regulation of RTK signaling by MIG-6 and SPRY2 is a delayed event because it requires
2. The features and functions of MIG-6 and SPRY2
2.1. MIG-6
2.2. SPRY2
In term of evolution, the
In
Beyond being an intrinsic inhibitor for Fgf signaling, Spry also regulates signaling driven by other RTKs like Egfr. The
3. Negative feedback regulation of RTK signaling by MIG-6 and SPRY2
3.1. Regulation of RTK pathways by MIG-6
Many growth factors can induce MIG-6 expression, including EGF, FGF, and HGF [9]. Upon induction, MIG-6 proteins rapidly and transiently accumulate in the cytoplasm, where they feed back to inhibit the activated RTK signaling (Figure 2]. The inhibition of EGFR/ErbB signaling by MIG-6 can occur at two molecular levels: one on the receptor itself, and another on the signaling molecules downstream of the receptor (Figure 2). Through its C-terminal EBR domain, MIG-6 directly binds to EGFR and other ErbB members [17, 19, 20, 58]. The interaction involves the kinase domain of EGFR or ErbB2 and requires their catalytic activities, but does not involve their C-terminal regions in which there are tyrosine residues essential for activating downstream signaling [20, 58]. Crystal structures reveal that the MIG-6 EBR domain binds to the distal surface of the carboxy-terminal lobe (C-lobe) in the kinase domain of EGFR [59]. The C-lobe is crucial in asymmetric EGFR dimer formation [60]; binding of MIG-6 to the C-lobe blocks the dimer interface thereby preventing EGFR activation [59]. MIG-6 coupling also promotes clathrin-mediated endocytosis of EGFR [61], an important mechanism for timely attenuation of ligand-induced EGFR activation [62, 63]. The region responsible for promoting EGFR endocytosis has been mapped to the endocytic domain (ED) of MIG-6 (see Figure 1A) [61], which mediates the binding of MIG-6 to the AP2 adaptor complex, a key component in forming clathrin-coated pits during endocytosis [63]. Interestingly, the non-receptor tyrosine kinase ACK1 also binds to EGFR upon EGF stimulation through a region sharing high homology with the MIG-6 EBR domain [21]. This interaction also regulates clathrin-mediated EGFR endocytosis and degradation [21, 64]. However, it is not clear whether MIG-6 and ACK1 cooperate in regulating EGFR turnover or whether they bind to EGFR in a mutually exclusive way to accomplish individual inhibitory roles under different circumstances. The internalized EGFR is guided to late endosome through the binding of MIG-6 to the endosomal SNARE complex component STX8, en route to degradation in the lysosome [61, 65].
The magnitude of MIG-6-mediated inhibition of EGFR signaling is likely maximized and integrated by the second level of molecular regulation, that is, direct inhibition of downstream signaling molecules (Figure 2). MIG-6 binds to the SH3 domain-containing protein GRB2 [14, 17], the key molecule in linking activated RTK to the intracellular signaling cascade; GRB2 brings RAS together with SOS to the phosphorylated receptor for activation [66]. Binding of MIG-6 may block GRB2’s interaction with activated EGFR and other RTKs or disrupt GRB2-SOS-RAS complex formation, thereby preventing activation of the RAS-MEK-MAPK pathway. MIG-6 also interacts with Src, the PI3K p85 subunit, PLCγ, and Fyn [17], although those interactions were demonstrated in an artificial system and their biological meaning remains to be determined. More complexity is likely in the dynamics of MIG-6-mediated RTK signaling regulation due to the interaction of MIG-6 with 14-3-3 proteins [12, 67], an adaptor family that may interact with diverse signaling molecules and regulate many biological activities [68]. Nonetheless, most of these direct downstream signaling regulations by MIG-6 remain largely speculation and require further investigation.
Assessing the effect of MIG-6 on RTK pathways other than those of the EGFR family, however, may provide insightful answers to such speculation, because direct regulation of the RTK itself by MIG-6 appears to be unique to the EGFR family. For instance, MIG-6 can be induced by HGF and function as negative feedback regulator of the MET pathway by inhibiting HGF-induced cell migration and proliferation [14], yet no physical interaction between MIG-6 and MET has been observed. Through its CRIB domain, MIG-6 can bind to and inhibit the activity of the Cdc42 small GTPase [12, 14], and this inhibitory activity is required for blocking of HGF-induced cell migration [14]. The CRIB domain also interacts with IκBα, thereby activating NFκB for transcriptional regulation of its target gene expression [15, 16]. Whether the inhibition of HGF-induced cell proliferation by MIG-6 is mediated by its ability to bind GRB2 or to bind other downstream molecules is still unknown. Negative feedback inhibition of other RTKs (such as FGFR and IGFR) by MIG-6 is also likely to be mediated by its inhibitory activities on the downstream signaling molecules rather than on the receptor itself.
The inhibitory activity of MIG-6 on RTK signaling seems to be modulated by phosphorylation; Liu et al. recently reported that MIG-6 can be phosphorylated by Chk1 upon EGF stimulation [67]. EGF activates Chk1 via the PI3K-AKT-S6K pathway, which in turn phosphorylates Ser251 of MIG-6 and results in inhibition of MIG-6 [67]. Thus, Chk1 counter-balances the EGFR inhibition of MIG-6, positively regulating EGFR signaling. Interestingly, Ser251 resides in the 14-3-3 binding motif of MIG-6 and its phosphorylation is likely involved in the MIG-6 and 14-3-3ζ interaction, because that interaction is abolished by Chk1 depletion [67]. In addition, two tyrosine residues (Tyr394 and Tyr458) in MIG-6 are phosphorylated by EGFR activation [69-71], but the underlying mechanism and the biological significance remain unclear.
3.2. Regulation of RTK pathways by SPRY2
SPRY2 renders another layer of modulation on RTK signaling via a negative feedback loop [10, 36, 37, 72]; its expression is induced by many activated RTKs including EGFR, FGFR, MET, and VEGFR [10, 72]. As with MIG-6, SPRY2-mediated regulation can occur on two levels: on the RTK itself and on the downstream signaling molecules (Figure 3). However unlike MIG-6, the most prominent inhibitory activity of SPRY2 is derived from its abilities to interact with downstream signaling molecules centering on the RAS-RAF-MAPK pathway, while its effect on the RTK itself seems to be indirect and may provide some signaling specificity for different RTKs [10, 36, 37].
Upon growth factor stimulation, SPRY2 translocates from the cytosol to the plasma membrane where it binds to phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] via the conserved SPRY domain [73-75]. Membrane translocation appears to be triggered by the activated Rac small GTPase and is essential for SPRY2 function [76]. The phosphorylation of the Tyr55 residue in SPRY2 is likely regulated by a SRC family kinase, which upon FGF stimulation is recruited to activated FGFR by FRS2 [77]. While Tyr55 phosphorylation enables the binding of SPRY2 to GRB2 via the SH2-binding motif in the N-terminus [78], the SH3-binding motif in its C-terminus may also play a role in the SPRY2-GRB2 interaction [39-41] (Figure 1B). The latter is likely regulated by the protein phosphatase 2A (PP2A), a serine/threonine phosphatase that interacts with Tyr55 and dephosphorylates certain serine residues in SPRY2 for permitting access of GRB2 to the SH3-binding motif on SPRY2 [41, 45]. Consequently, the binding of SPRY2 to GRB2 prevents the recruitment of the GRB2-SOS complex to the FRS2 adaptor or SHP2 phosphatase proximal to the activated RTK, thereby inhibiting the activation of RAS and its downstream molecules [10, 36, 39, 77, 78]. The RTK-RAS-RAF-MAPK/ERK pathway can also be inhibited by direct binding of SPRY2 to RAF [75, 79, 80]. On the other hand, TESK1 negatively regulates SPRY2 inhibitory activity by interfering with the SPRY2 interaction with GRB2 and PP2A [81], while DYRK1A binding results in Thr75 phosphorylation on SPRY2 and suppression of SPRY2 inhibitory activity, thereby enhancing FGF-induced ERK activation [42].
The regulation of EGFR signaling by SPRY2 appears to be more complicated than that of FGFR signaling, because SPRY2 can indirectly influence the turnover of EGFR through its interaction with CBL (Figure 3) [10, 36, 37]. This regulation is mediated by the SH2-binding motif, which includes Tyr55 in the N-terminus of SPRY2. When Tyr55 is phosphorylated, SPRY2 interacts with the SH2-domain on CBL, and prevents CBL from binding to the activated EGFR, thereby interfering with CBL-mediated EGFR endocytosis and degradation [43, 82-84]. This action can prolong the activation of EGFR and the downstream RAS-RAF-MAPK pathway, contrary to the direct inhibitory activity of SPRY2 on the downstream signaling molecules. These two opposite activities render SPRY2 a delicate role in fine-tuning EGFR signaling, negative in some situations and positive in others, depending on the threshold and balance of these two activities.
It is conceivable that RTKs such as MET and PDGFR that are also substrates of CBL might also be affected by SPRY2 like that of EGFR [8, 85], while non-CBL-substrate RTKs like FGFR appears unaffected by SPRY2-CBL interaction [36]. However, it is known that MET protein level is not affected by SPRY2 overexpression that inhibits HGF-induced ERK and AKT activation, indicating that the effect of SPRY2-CBL interaction on EGFR and on MET might not be the same [72, 86]. The sequestration of CBL by SPRY2 can also affect downstream signaling molecules, as it may free proteins like GRB2 from CBL-mediated ubiquitination and degradation [85]. Furthermore, SPRY2 itself can be ubiquitinylated and degraded by the CBL binding, thereby influencing the RTK signaling [83].
4. Tumor suppressor role of MIG-6 and SPRY2 in cancer
4.1. MIG-6 as a tumor suppressor gene
Human chromosome 1p36, a locus frequently associated with many human cancers [87-92], harbors the
Unlike many other tumor suppressor genes whose expression is directly regulated by epigenetic modification of their promoter regulatory elements [3], the silencing of
Besides loss or reduction of expression,
4.2. SPRY2 as a tumor suppressor gene
There is compelling evidence supporting SPRY2 as a tumor suppressor [99]. The
Downregulation of SPRY2 expression may be attributed to DNA methylation; hypermethylation of its promoter has been observed in prostate cancer [100], hepatocellular carcinoma [86], endometrial carcinoma [107] and B-cell lymphomas [109, 110]. However, controversial results have also been reported, since no methylation in
5. The impacts of MIG-6 or SPRY2 activity on RTK signaling in cancer
The loss of MIG-6 and SPRY2 feedback regulation leads to prolonged RTK signaling activation and may contribute to hallmark activities of cancer [113]. Ectopic expression of MIG-6 results in decreased phosphorylation of EGFR/ErbBs and downstream ERK/MAPK and AKT, and it inhibits cell proliferation in several cancer types [19, 20, 65, 96, 114]. In contrast, down-regulation of
Nonetheless, a study of NCI-60 cell lines, which cover a broad spectrum of cancer types, revealed that
There is limited evidence that
6. Conclusion and perspective
The negative feedback loops to receptor tyrosine kinases of MIG-6 and of SPRY2 provide crucial intersecting points for tumor suppressor genes and oncogenes, placing them in the same signaling networks for regulating physiologic and oncogenic activity. This sophisticated regulatory mechanism allows timely attenuation of RTK signaling by those TSGs, and ensures a proper cellular response following growth factor stimulation. MIG-6 and SPRY2 are no more than the representatives for the class of TSGs involved in RTK signaling regulation, and we believe there are more such TSGs in the human genome either remain to be discovered or have already been revealed (such as other SPRY family members). To date, most of the studies on MIG-6 and SPRY2 have focused on their activity in regulating selected RTKs such as EGFR, MET and FGFR. Their roles in regulating most other RTKs and the clinical relevance of such regulation remain largely unknown. Also, there are conflicting results on how MIG-6 and SPRY2 may regulate the RTK signaling, on both the receptor and the downstream signaling levels, and further studies are required to address those issues. Although EGFR and other RTKs like MET appear to be regulated slightly differently by MIG-6 and SPRY2, it remains to be determined to what extent these TSGs may provide signaling specificity to different RTKs. Beyond all aforementioned issues, a broader question might be why an RTK network needs multiple negative feedback regulators to fine-tune its signaling; might the regulators function differently for each RTK in a temporal and spatial manner i.e. at right place, on right time and for right target?
While conventional mechanisms such as mutation or promoter methylation may contribute to the inactivation of MIG-6 or SPRY2 tumor suppressor roles, their activities are also likely silenced by unconventional means in cancer. For example, in most cancer types investigated so far,
Clinically, it is important to understand how tumor suppressor genes may affect the therapeutic outcome of RTK-targeted therapies, which can be effective in treating certain human cancers. In a limited number of studies, low expression of
Acknowledgments
Thanks to David Nadziejka for critical reading and technical editing, and to the Van Andel Foundation for the financial support.References
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