Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Serine/Threonine-Protein Kinase SMG1

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101805

Synonyms

Historical Background

In 1993, the Anderson lab reported that loss of function mutations affecting seven Caenorhabditis elegans smg genes (smg-1∼smg-7) eliminates nonsense-mediated mRNA decay (NMD), an mRNA surveillance mechanism which degrades mRNA containing nonsense mutation (Pulak and Anderson 1993). Later, the Anderson lab reported cloning of C. elegans smg-2, a nematode ortholog of UPF1, and in vivo phosphorylation of SMG-2 at 1999 (Page et al. 1999). SMG-2/UPF1 is an evolutionally conserved central component of NMD. In that paper, they discussed smg-1 gene product is a strong candidate of a kinase for the phosphorylation of SMG-2 and submits a SMG-1 sequence in the public database at early September 1999 (Page et al. 1999). They report smg-1 cloning and demonstrate that SMG-1 kinase activity was essential for NMD in vivo and SMG-2 phosphorylation in vitro at 2004 (Grimson et al. 2004).

Part of the human SMG1 gene product firstly reported in 1996 as an atypical PKCλ/ι (aPKCλ/ι) interacting protein, LIP (lambda-interacting protein) (Diaz-Meco et al. 1996). However, this LIP cDNA, that encoded a 713 amino acid (aa) protein, contained a frameshift mutation and the carboxyl (C) -terminus FAT-C (FRAP, ATM, and TRRAP-C-terminus) domain which conserved among PI3-kinase related protein kinases (PIKKs), was not identified. In 1997, another fragment of the SMG1 gene product was identified that encoded a 1302-aa protein and was named KIAA0421. KIAA0421 contained most LIP sequences and contained C-terminus FAT-C domain (Ishikawa et al. 1997).

Three groups have independently cloned and reported the protein kinase activity of human SMG1. In 2001, the Fields lab reported a partial sequence of human SMG1 that encoding 3031 aa protein, as C. elegans SMG-1 related protein. This protein showed in vitro phosphorylation of 4E-BP1 and UPF1 by immunoprecipitated SMG1 (Denning et al. 2001). The same year, the Ohno lab reported the full-length sequence for human SMG1. This gene encoded a 3657 aa protein that was a novel PIKK. They showed the involvement of SMG1 in mammalian NMD, identified the SMG1 mediated-phosphorylation of UPF1 at Ser-1078 and Ser-1096 in vitro and in vivo, and showed the complex formation of SMG1 and UPF1 in cell lysate (Yamashita et al. 2001). In 2004, the Abraham lab reported that a splice variant of human SMG1, encoding a 3521 aa novel PIKK “ATX”. They showed the activation of SMG1 by DNA damage, the SMG1 mediated-phosphorylation of p53 at Ser-15 and also demonstrated the involvement of SMG1 in genotoxic stress-induced phosphorylation of p53 at Ser-15 (Brumbaugh et al. 2004).

Assembly of the human genome sequence revealed that SMG1 gene is represented eight times within the human genome with a 97∼98% of sequence identity (SMG1 and SMG1 pseudogene (SMG1P) 1∼7). The annotated SMG1 gene encodes 3661 aa protein, which has a 6 aa difference from the 3657-aa isoform identified earlier by the Ohno lab and a 108-aa difference from the 3521-aa isoform identified in the Abraham lab. Except SMG1P4, SMG1P1∼7 express long noncoding (lnc) RNA (Martin et al. 2004). Note that the 5′ of 719 nucleotides encoding 131 aa of SMG1 cDNA reported the Ohno lab comes from SMG1P5, and 5′ of 102 nucleotides encoding 4 aa of SMG1 cDNA reported the Abraham lab comes from SMG1P2. Consequently, care needs to be taken with microarray and RT-qPCR probe design to avoid detection of the lncRNA from these pseudogenes instead of SMG1 mRNA. Moreover, SMG1 expression profile data of might need to be reevaluation if non-specific probes were used.

According to immunological analysis, the human SMG1 has at least two isoforms, p430 and p400. The antibody against the amino terminal 106 amino acids of the 3657-aa protein recognizes only the SMG1 p430 isoform suggesting the SMG1 p400 isoform lacks this amino-terminal sequence (Yamashita et al. 2001). Although the two isoforms are conversed among mammals, the biological significance of the sequence variation at the amino terminus of SMG-1 remains unclear.

In addition to nematode and mammals, the functional significance of SMG1 for NMD is reported in various organisms including the insect (Drosophila melanogaster) (Gatfield et al. 2003) and the basal land plant (Physcomitrella patens) (Lloyd and Davies 2013). Based on analysis of the genome sequences of various species, SMG1 should have been present in the last common eukaryotic ancestor. However, there are multiple independent losses of SMG1 in the fungi and excavata branches, as well as in some plant (e.g., Arabidopsis thaliana) (Lloyd and Davies 2013) (Fig. 1a).
Serine/Threonine-Protein Kinase SMG1, Fig. 1

SMG1 is an evolutionally conserved PIKK. (a) Evolutionary tree of selected eukaryotes rooted adapted from (Lloyd and Davies 2013). SMG1, SMG8, and SMG9 cluster together in most of the species analyzed, and are present in the most recent ancestor (LECA). The oomycetes Phytophthora nicotianae, the red algae Cyanidioschyzon merolae, the brown algae Ectocarpus siliculosus, and the excavates Trypanosoma brucei. (b) Schematic structure of human SMG1, SMG8, and SMG9. α-SOLENOID, FAT (FRAP, ATM and TRRAP), FRB (FKBP12-rapamycin binding), PIKK and FAT-C domains of SMG1 are indicated. NTPase domain of SMG9 is indicated

Structure and Biochemical Characterization of SMG1 as a PIKK Family Kinase

SMG1 belongs the member of the PIKKs that include ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3 related), mTOR (mammalian target of rapamycin), DNA-PKcs (DNA-dependent protein kinases catalytic subunit), and TRRAP (transformation/transcription domain-associated protein) (Baretic and Williams 2014). With the exception of TRRAP, PIKKs have intrinsic serine/threonine kinase activity. PIKKs can be distinguished from other protein kinases by their unique catalytic domain (PIKK domain) similar to lipid PI3K catalytic domain, FAT-C domain and large molecular weight (270–470 kDa) (Izumi et al. 2012b; Baretic and Williams 2014). The unique structural feature of SMG-1 relative to other PIKKs is a large insert between the PIKK and FAT-C domains (Fig. 1b) (Izumi et al. 2012b; Baretic and Williams 2014). The conservation of this SMG1 insert across all species examined to date suggests its importance. However, this insert is not required for the intrinsic kinase activity of SMG1 (Morita et al. 2007), and it has no reported function apart from an interaction with aPKCλ/ι (Diaz-Meco et al. 1996). It is also notable that the binding of this insert with LIP and aPKCλ/ι failed to capture the 3031-aa partial-length, or the 106-3657-aa full-length, SMG1 (Denning et al. 2001; Yamashita et al. 2001).

SMG1, ATM, ATR, and DNP-PKcs are termed S/T-Q-directed kinase, based on strong preferences for the phosphorylation of serine (S)/threonine (T) residue followed by a glutamine (Q) residue (Yamashita et al. 2001; Izumi et al. 2012b). Similar to other PIKKs, SMG1 exhibit a preference for Mn2+ ions over Mg2+ ions and is inhibited by wortmannin, IC50; 60∼105 nM in vitro/1∼2 μM in vivo, and caffeine, IC50; 0.3 mM in vitro, but is not inhibited by staurosporine and rapamycin in vitro (Denning et al. 2001; Yamashita et al. 2001; Brumbaugh et al. 2004). Although a SMG1 specific inhibitor is not commercially available, SMG1 preferential inhibitor, which have tenfold higher EC50 value, ∼0.1 μM, than mTOR, ∼1 μM, in vivo, is reported (Gopalsamy et al. 2012).

In mammalian cells, SMG1 forms a stable heterotrimeric complex termed SMG1C (SMG1 complex) with SMG8 and SMG9 (Yamashita et al. 2009; Arias-Palomo et al. 2011; Fernandez et al. 2011). Both the SMG8 and SMG9 genes are present in most organisms that contain the SMG1 gene, but are absent in all species that do not contain SMG1 (Fig. 1a). Mammalian SMG8 does not have any significant protein motifs (Yamashita et al. 2009), and is highly expressed in breast cancer (Wu et al. 2001). SMG-9 comprises a C-terminal putative nucleotide-triphosphatase domain preceded by an intrinsically disordered N-terminal region (Yamashita et al. 2009; Arias-Palomo et al. 2011; Fernandez et al. 2011). Both SMG8 and SMG9 can be a substrate of SMG1, but phosphorylation site(s) and function of this phosphorylation are unknown (Yamashita et al. 2009). More than 90% of SMG1 exists as an approximately 600-kDa SMG1C and the remainder of SMG1 exists as an approximately 470 kDa SMG1-SMG9 complex, and no detectable monomeric SMG1 is observed in mammalian cells (Fernandez et al. 2011). On the other hand, SMG9 assembles into several complexes apart from SMG1C, SMG9-SMG9 complexes, and SMG8-SMG9 complexes (Fernandez et al. 2011). The existence of SMG8-SMG9 complexes indicates that an association between these two proteins may also regulate the interaction with SMG1 and the assembly of SMG1C (Fernandez et al. 2011). Consistent with this hypothesis, SMG9 is essential for the SMG8 binding with SMG1 (Yamashita et al. 2009; Arias-Palomo et al. 2011; Fernandez et al. 2011). Therefore SMG9 complexes, and probably SMG8-SMG9 complexes as well, may function as intermediaries mediating the assembly of SMG1C (Fig. 2). This method of SMG1C assembly probably ensures the formation of kinase repressed SMG1C since SMG8 represses SMG1 kinase activity (Yamashita et al. 2009; Arias-Palomo et al. 2011). Moreover, removal of SMG8 might be a mechanism by which SMG1 is activated (Fig. 2).
Serine/Threonine-Protein Kinase SMG1, Fig. 2

Model of the assembly of the SMG1 complex, and how the SMG1C complex regulates SMG1 kinase activity

PIKKs have a common regulatory molecular chaperone complex that consists of an HSP90, R2TP (RUVBL1-RUVBL2-RPAP3 [Tah1] -PIH1D1 [Pih1]) complex, and a TTT (TEL2-TTI1 [SMG10] -TTI2) complex (Izumi et al. 2012b; von Morgen et al. 2015). These complexes are associated with PIKK abundance and complex formationa (Takai et al. 2007; Izumi et al. 2010). The CK2 (Casein kinase 2) -mediated phosphorylation of the DSDD motif of TEL2 in the TTT complex, which recognizing by PIH1D1, links the R2TP complex and HSP90 for PIKK (Fig. 3) (von Morgen et al. 2015). The ATPase activity of HSP90, RUVBL1, and RUVBL2 are involved in the SMG1 abundance, SMG1-mediated UPF1 phosphorylation, and the complex formation of SMG1 with NMD factors (Takai et al. 2007; Izumi et al. 2010; Izumi et al. 2012a). SMG1 also associates with the URI-RPB5 complex most likely through R2TP and RPB5 at a minimum is involved in NMD (Izumi et al. 2010).
Serine/Threonine-Protein Kinase SMG1, Fig. 3

Model of the TTT, R2TP, and HSP90 complex act for SMG1 adapted from (Izumi et al. 2012b; von Morgen et al. 2015). Three common PIKK regulators, the TTT, R2TP, and Hsp90 complex interact with one another. RPB5 and URI are shared interactors of the TTT, R2TP, and Hsp90 complex. The interaction between the R2TP complex and the TTT complex is mediated by PIH1D1 in a Tel2 phosphorylation-dependent manner. The RPAP3 C-terminal domain directly connect the HSP90 dimer to the R2TP complex

SMG1 in Nonsense-Mediated mRNA Decay (NMD)

As described in historical background section, SMG1 functions in NMD (Schweingruber et al. 2013). NMD selectively degrades premature termination codon (PTC)-containing mRNAs, which can be generated by gene mutations, splicing or transcription errors. This NMD process suppresses the production of potentially harmful or nonfunctional polypeptides and ensures the accuracy of gene expression (Schweingruber et al. 2013). NMD also plays a more general role in regulating gene expression by controlling the decay of a significant fraction of mRNAs containing uORF, 3′UTR intron, seleno-cysteine codon (UGA), and PTC-containing alternative exons (Schweingruber et al. 2013).

SMG1 plays an essential role in NMD by phosphorylating UPF1 helicase, a central regulator of NMD (Schweingruber et al. 2013). When a ribosome recognizes a PTC, SMG1, UPF1, and eukaryotic releasing factors (eRF1 and eRF3) assemble to form the SMG1C-UPF1-eRF1-eRF3 (SURF) complex on the PTC-recognizing stalled ribosome (Kashima et al. 2006; Yamashita et al. 2009; Izumi et al. 2010). If an exon junction complex (EJC), a multiprotein complex deposited on an exon-junction in a splicing dependent manner, exists downstream of the PTC, the SURF associates with the EJC through UPF2-UPF3 to form DECay InDuing (DECID) complex (Kashima et al. 2006; Yamashita et al. 2009; Izumi et al. 2010). The DECID complex formation establishes PTC recognition and induces SMG1-mediated UPF1 phosphorylation (Kashima et al. 2006; Yamashita et al. 2009; Izumi et al. 2010). Phosphorylated-UPF1 most likely marks PTC-containing mRNA (Johns et al. 2007; Yamashita et al. 2009; Kurosaki et al. 2014). Since SMG8 is a kinase repressor subunit of SMG1 and is required for the DECID formation, the presence of SMG8 ensures recruitment of kinase activity repressed SMG1 to SURF, thereby avoiding undesirable UPF1 phosphorylation (Yamashita et al. 2009; Arias-Palomo et al. 2011). It is notable that UPF2 can be recruited to SMG1C independently of UPF1, which may permit downstream exon junction independent NMD (Melero et al. 2014; Lopez-Perrote et al. 2016). This observation also implies that UPF2 binding to SMG1 is insufficient for SMG1 activation. Another protein, DHX34 may also be involved with formation of the SMG1C, UPF1 and UPF2 complex (Melero et al. 2016).

Phosphorylated UPF1 recruits NMD factors that recognize its phosphorylation, including SMG6 and the SMG5-SMG7 complex (Ohnishi et al. 2003; Okada-Katsuhata et al. 2012; Chakrabarti et al. 2014). SMG6 has intrinsic endonuclease activity (Huntzinger et al. 2008; Eberle et al. 2009), whole the SMG5-SMG7 complex recruits the CCR4-NOT deadenylase complex through the C-terminus of SMG7 (Loh et al. 2013). Hence, SMG6 and the SMG5-SMG7 complex advances subsequent decay processes (Huntzinger et al. 2008; Eberle et al. 2009; Loh et al. 2013). Taken together with above observations, SMG1-mediated UPF1 phosphorylation is an essential late limiting step in NMD (Fig. 4). Note that SMG6 binds independently with UPF1 phosphorylation in vitro and most likely in vivo, and that this phospho-independent binding is functionally important for NMD (Chakrabarti et al. 2014; Nicholson et al. 2014). Phospho-specific binding of SMG6 and UPF1 can be captured by only when using endogenous proteins or when either one is exogenously expressed (Ohnishi et al. 2003; Okada-Katsuhata et al. 2012). An alternative model for the role of UPF1 phosphorylation during NMD is also reported (Cho et al. 2013a; Durand et al. 2016). Although Upf1 is identified as a substrate of other PIKKs, the function of SMG1 in NMD cannot be compensated with other PIKKs.
Serine/Threonine-Protein Kinase SMG1, Fig. 4

Model of the molecular mechanism of nonsense-mediated mRNA decay in mammals. PTC recognition is established by the formation of mRNA surveillance complexes called “SURF” and “DECID”. These complexes occur during the initial round of translation at sites containing a PTC-recognizing ribosome and a downstream exon-junction complex (EJC). During translation termination, the SURF complex composed of SMG1C (SMG1/SMG8/SMG9 complex), UPF1, and eRF detects the downstream EJC and forms a DECID complex, which induces SMG1-mediated UPF1 phosphorylation. Phosphorylated UPF1 recruits mRNA decay factors to degrade mRNA

Roles of SMG1 Beyond NMD

UPF1 is a multifunctional protein that is involved not only in NMD, but also histone mRNA decay, Staufen-mediated mRNA decay, Regnase-1-associated mRNA decay, telomere leading-strand replication, and DNA polymeraseδ-mediated DNA repair in addition to NMD (Izumi et al. 2012b). Of these functions, SMG1 is thought to regulate Staufen-mediated mRNA decay (Cho et al. 2013b). Intriguingly, instead of SMG1 there are alternative PIKKs for UPF1 associated with histone mRNA decay (ATR and DNA-PK), DNA polymeraseδ-mediated DNA repair (ATR), and telomere leading-strand replication (ATR) (Izumi et al. 2012b).

In addition to UPF1 associated role, SMG1 is implicated in other stress responses, including DNA damage (Brumbaugh et al. 2004; Meslin et al. 2011; Xia et al. 2011; Gubanova et al. 2013), oxidative stress (Gehen et al. 2008; Brown et al. 2011), hypoxia (Chen et al. 2009), TNFα signaling (Oliveira et al. 2008), Parkinson’s disease-associated α-synuclein phosphorylation (Henderson-Smith et al. 2013), and sorafenib sensitivity (Nam et al. 2014). SMG1 is activated by IR, UV, or DNA double strand break caused by restriction enzyme and phosphorylates p53 in a similar manner to that of ATM and ATR (Brumbaugh et al. 2004; Gewandter et al. 2011). Moreover, SMG1 knockdown causes spontaneous DNA damage and sensitizes cells to IR (Brumbaugh et al. 2004). SMG1 is also associated with telomeres and protect telomeres by inhibiting the association between telomeric repeat-containing RNA (TERRA) with telomeric DNA (Azzalin et al. 2007) (Fig. 5). In most of these cases, the detailed mechanisms by which SMG1 and its substrates are activated have not been elucidated and need to be resolved in the future.
Serine/Threonine-Protein Kinase SMG1, Fig. 5

SMG1 is a multifunctional protein. SMG1 is identified as mediator of various stress signaling. Unidentified specific substrates of SMG1 should react through distinct mechanisms

Homozygous SMG1 gene trap mice have an early embryonic lethal phenotype, while haploinsufficient mice have elevated rates of cancer and inflammation-related cytokines (e.g., IL-2, IL-6, IL-10, and TNFα) (McIlwain et al. 2010).

In contrast, SMG1 null mutants in C. elegans and D. melanogaster are viable. SMG1 inactivation increases oxidative stress resistance and longevity in analogy to TOR in C. elegans (Masse et al. 2008). On the other hand, SMG1 and mTORC1 act antagonistically to regulate response to injury and growth in planarians (Schmidtea mediterranea) (Gonzalez-Estevez et al. 2012).

Summary

SMG1 is a PIKK family member kinase forms a stable heterotrimeric complex with SMG8 and SMG9, termed SMG1C. SMG1C is conserved among various eukaryotes including metazoan and plant. SMG1 plays an essential role in NMD by phosphorylating specific serine/threonine residues of UPF1. When a ribosome is stalled at a PTC, SMG1 forms the SURF (SMG1-UPF1-eRF1-eRF3) complex on the PTC recognizing ribosome. If an EJC exists downstream of the PTC, the SURF associates with the EJC through UPF2-UPF3 to form the DECID complex. The DECID complex establishes PTC recognition and induces the SMG1-mediated UPF1 phosphorylation to recruit mRNA decay factors. SMG1 also implicates various cellular functions including Staufen-mediated mRNA decay, DNA damage, oxidative stress, hypoxia, TNFα signaling, and sorafenib sensitivity. The detailed mechanisms of these SMG1 functions are yet to be resolved.

Notes

Acknowledgments

I would like to thank Ms. Kae Suzuki for reading manuscript.

Funding

This project was funded by the Japan Society for the Promotion of Science KAKENHI [20405020].

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular BiologyYokohama City University School of MedicineYokohamaJapan