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Indian Journal of Cancer, Vol. 48, No. 3, July-September, 2011, pp. 351-360 Review Article The Smad family and its role in pancreatic cancer P Singh1, JD Wig2, R Srinivasan3 1 Cancer Genetics Unit, Hormones and Cancer Group, Kolling Institute of Medical Research, NSW, 2006, Australia Code Number: cn11091 PMID: 21921337 DOI: 10.4103/0019-509X.84939 Abstract One of the major signaling pathways that determine the tumor aggression and patient outcome in pancreatic cancer is the transforming growth factor-beta (TGF-ß) pathway. It is inactivated at various levels in pancreatic cancer and plays a dual role in tumor initiation and progression. The Smad family of proteins transduce signals from the TGF-ß superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. This review discusses the structure, function and regulation of various participating Smad family members, and their individual roles in determining the progression and outcome of pancreatic cancer patients, with a special emphasis on Smad4.Keywords: Pancreatic cancer, smad family, Smad4, Smad6, Smad7, transforming growth factor-beta Introduction The members of the transforming growth factor-β (TGF-β) family control growth, differentiation and apoptosis of cells and have important functions during embryonic development. The TGF-β family ligands initiate downstream signaling events by activation of transmembrane serine-threonine kinase receptors, namely, TGF-β type I receptor (TbRI) and TGF-β type II receptor (TβRI) [Figure - 1]. On ligand binding, TβRII becomes constitutively active, heterodimerizes with TβRI and transphosphorylates its GS domain, resulting in its activation. [1],[2] Once activated, TβRI phosphorylates a class of molecules known as receptor-regulated Smads (R-Smads) at an SSXS motif at their C-terminal end. [3] Active, phosphorylated Smad2 or Smad3 heterodimerize with Smad4, translocate to the nucleus and regulate transcription. [4],[5] Smad6 and Smad7 are the negative regulators of TGF-β pathway and act by blocking R-Smads' interaction with TβRI, phosphorylation by TβRI or heterodimerization with Smad4. [6],[7] Although Smad4 is inactivated in many cancers, its specificity for pancreatic cancer makes it one of the most extensively studied markers for pancreatic cancer. It is lost in 55% of the cases, and its loss often predicts a poorer prognosis. Besides Smad7, which is emerging as a new molecule of consequence in this disease, other components of the Smad family do not have a significant role to play. TGF-β itself is one of the important growth factors in pancreatic cancer, which, in the event of Smad4 loss, through alternative pathways, supports tumor growth and progression. Discovery and Nomenclature of Smads Proteins belonging to the Smad family were first identified in the fruit fly Drosophila melanogaster in the mid 1990s, where an intracellular protein named Mad mediates the signaling of decapentaplegic (dpp), a member of the TGF-β superfamily corresponding to mammalian bone morphogenetic protein 2 or 4 (BMP-2/4). [8] The discovery of orthologous proteins in Caenorhabditis elegans as well as in vertebrates soon followed, which paved the way to the discovery of a whole new family of proteins, the Smad family, which functions as important mediator of the TGF-β signaling pathway. The term "Smad" is derived from a combination of the gene name from two orthologous proteins sma from Caenorhabditis elegans, and Mad from Drosophila melanogaster. [9] The first Smad to be discovered was Smad4, or DPC4 (deleted in pancreatic cancer 4). [10] General Structure of Smads Smads consist of two conserved domains: The N-terminal Mad Homology domain1 (MH1 domain) and the C-terminal Mad Homology domain 2 (MH2 domain), joined together by a linker region, which is full of regulatory sites [Figure - 2]. MH1 domain has DNA-binding activity (except in the major splice form of Smad2, which contains an insert that prevents DNA binding), whereas the MH2 has transcriptional activity. [11] Receptor-mediated phosphorylation appears to relieve these two domains from a mutually inhibitory interaction. The L3 loop and the α-helix-1 (αH-1) in the MH2 domain of a R-Smad and the L45 loop in the kinase domain of a type I receptor specify the Smad-receptor interaction. [12] The αH-2 domain of Smads specifies interactions with certain DNA-binding cofactors. [13],[14],[15] A highly basic surface patch conserved around the L3 loop of all R-Smads and a complementary surface pattern on TβR-I kinase domain may facilitate receptor-Smad recognition. [16] This L3 loop is absent in Smad4. [17] The linker region has a regulatory function and contains phosphorylation sites for Erk and MAPKs, consensus sites for calcium-regulated kinases and one prolin-tyrosine (PY) motif for recognition by WW domains for ubiquitination or sumoylation of the Smads. Members of the Smad Family There are eight different Smads (Smad 1-8) in mammalian cell populations, which are classified into three categories: (i) receptor-regulated or regulatory Smads (R-Smads), which include Smads 1, 2, 3, 5 and 8, (ii) common Smad (Co-Smad), i.e. Smad 4 and (iii) inhibitory or anti-Smads (I-Smads), which are Smad 6 and Smad 7. The general structure of Smads is more or less the same, with a few differences among different categories of Smads, which influence their respective functions [Figure - 3]. Receptor-Regulated Smads or R-Smads R-Smads directly interact with activated TβRI in the receptor complex and, as a result, are phosphorylated at two of the three serine residues in a C-terminal SSXS motif [18] [Figure - 4]. Of the five R-Smads, Smad2 and Smad3 mediate activin and TGF-β signal transduction, while Smad1, Smad5 and Smad8 mediate BMP signals. [19],[20] Following phosphorylation of their MH1 domain, R-Smads can form oligomers at different stochiometries. Early experiments indicated that oligomeric Smads are trimers. [21],[22] Equilibrium centrifugation and crystallographic studies have confirmed this in the case of Smad3, [23],[24] but a dimeric configuration for the Smad2-Smad4 complex has also been proposed. [25] Therefore, different R-Smad-Co-Smad oligomers with distinct stoichiometries are possible. Once activated, Smad heterooligomers translocate to the nucleus, where they control target gene expression in a cell type-specific manner through interactions with other transcription factors, corepressors and coactivators. Studies with Smad4-null cell lines have shown that Smad2 and Smad3 are able to translocate to the nucleus on their own, but are unable to activate reporter genes on their own, suggesting that the whole R-Smad/Co-Smad complex is essential for transcriptional regulation. [26] Common Smad or Co-Smad There is only one Co-Smad, i.e. Smad4. The only other Co-Smad is Smad4β, found in Xenopus laevis. [27] Smad4 is recognized as a key tumor suppressor as it is defective in a number of cancers. It interacts with Smads 1, 2, 3 and 5 and hence participates in the intracellular signaling pathways of all three classes of TGF-β ligands. [19] This indicates that wild-type Smad4 in the TGF-β signal pathway may be critical in maintaining an environment that inhibits tumorigenesis. The SMAD4 gene is located on the long (q) arm of chromosome 18 at position 21.1, [28] and covers the region from 46,810,610 to 46,860,144 base pairs. The size of the whole gene is 49,539 bases, and it lies on the plus stand of DNA and transcribes 3220 nucleotides mRNA. The gene translates into a protein of molecular weight of 60,439 Daltons and contains 552 amino acids in its structure. Earlier, it was known to contain one to 11 exons, but recent mutational studies have led to the discovery of another exon that lies upstream of exon 1 and is named exon 0. [29] It belongs to the Dwarfin family of proteins, which harbor two conserved amino- and carboxyl-terminal domains known as MH1 and MH2, respectively. Smad4 in the basal state is found mostly as a homooligomer, most likely a trimer. On activation of R-Smads, it forms a heterooligomer with them, translocates into the nucleus and acts as a transcription factor. Anti-Smads or Inhibitory Smads or I-Smads The inhibitory Smads, Smad6 and Smad7, act antagonistically, abrogating TGF-β signal transduction. They contain an MH2 domain but have very little similarity to the cannonical MH1 domain of other Smads [Figure - 4]. Smad7 inhibits Smad phosphorylation by occupying type I receptors for TGF-β, Activin and BMP. [11],[30] Mouse Smad7 preferentially inhibits Activin and TGF-β signaling over BMP signaling, while the reverse is true of a Xenopus Smad7 homolog. [31] Smad7 appears to reside predominantly in the nucleus at basal state and translocates to the cytoplasm upon TGF-β stimulation. [32] Smad6 preferentially inhibits BMP signaling by a mechanism different from that of Smad7. [33],[34] When expressed at levels that are sufficient for inhibition of BMP signaling but not TGF-β signaling, Smad6 does not interfere with receptor function but competes with Smad4 for binding to receptor-activated Smad1 and yields inactive Smad1-Smad6 complexes. Overexpression of Smad4 can outcompete Smad6 and rescue BMP signaling. [33] At higher expression levels, Smad6 can mimic Smad7 and inhibit signaling by BMP and TGF-β receptors. [7] The expression of both Smad6 and Smad7 is increased in response to BMP, Activin and TGF-β, suggesting their roles in negative feedback of these pathways. [34],[35] The expression of Smad7 can also be increased by pathways that negatively regulate TGF-β signaling, e.g. interferon-γ (IFN-γ), acting via the Jak1 tyrosine kinase and the Stat1 transcription factor, providing a basis for the known antagonism between TGF-β and IFN-γ in the regulation of immune cell functions. [36] Similarly, in response to the proinflammatory cytokines, tumor necrosis factor-α and interleukin-1β activate Smad7 expression via the NF-κ B/RelA transcription factor. [37] Smad Activation Inactive, cytoplasmic Smads are intrinsically autoinhibited through an intramolecular interaction between the MH1 and MH2 domains. [38] Receptor-mediated phosphorylation induces conformational changes that relieve the autoinhibition and expose buried epitopes on to the surface, enabling Smads to interact with other components important for nuclear import, transcriptional regulation or degradation. Smad2 and Smad3, in their unphosphorylated and inactive form, reside predominantly in the cytoplasm bound to microtubule filaments [39] and filamins. [40] TGF-β signaling induces their dissociation by phosphorylating their C-terminal domains by TβRI receptor. TβRI receptor is associated with a FYVE domain containing scaffolding protein named SARA (Smad anchor for receptor activation). [41] Another cytoplasmic protein named PML (promyelocytic leukemia tumor suppressor) physically interacts with Smad2/Smad3 and SARA and is required for the association of Smad2/Smad3 with SARA. [42] SARA interacts with the MH2 domain of inactive Smad2 and Smad3, targeting them to early endosomes and aiding in their recruitment to the receptors, thus promoting Smad phosphorylation and TGF-β signaling. [43] On ligand binding, the activated type I and II receptors may be internalized via clathrin-coated pits into early endosomes that contain SARA along with Smad2/3. PML expression is induced by TGF-β and it is required for the accumulation of SARA and the TGF-β receptors in the early endosomes. Several other accessory/scaffolding proteins like SARA have been discovered for the TGF-β pathway R-Smads, e.g. axin and disabled2 (Dab2), [44],[45] but no accessory proteins have yet been discovered for the BMP-pathway Smads. These regions, where two types of receptors are found in combination with SARA, are called "Smad signaling centers" [Figure - 5]. Regulation of the Activation Process TGF-β signaling is modulated at multiple levels. Extracellular ligand trapping molecules or antagonists, including gremlin, noggin, chordin (all members of DAN/Cerberus protein family) and follistatin, can block ligand binding to the receptors. A pseudoreceptor BAMBI (BMP and Activin membrane bound inhibitor) extracellularly resembles a type I receptor but lacks the cytosolic kinase domain, traps and thus blocks activation by TGF-β ligands. [46] Posttranslational regulation of Smads, through a ubiquitin-mediated proteasomal degradation pathway, can profoundly affect signaling. [47],[48] Smad6 and Smad7 inhibit the Smad-mediated signaling; Smad7 by interacting with the type I receptor while Smad6 by competing with the activated R-Smads for heteromeric complex formation with co-Smad4. [49] c-Ski and SnoN, members of the Ski family of protooncoproteins, can antagonize TGF-β signaling through direct interactions with Smad4 and R-Smads. [50] Phosphorylation of Smads in the MAP kinase sites at the linker region attenuates ligand-induced nuclear translocation. Dephosphorylation of the Smads by as yet unidentified phosphatases may be another mechanism for the termination of Smad signaling. Phosphorylation of R-Smads by Other Signaling Pathways: A Cross-Talk between Different Pathways The linker region connecting the MH1 and MH2 domains is less conserved between different Smads, but contains several important regulatory peptide motifs, including potential phosphorylation sites for mitogen-activated protein kinases (MAPKs), Erk-family MAP kinases, [51] the Ca 2+ /calmodulin-dependent protein kinase II (CamKII) [52] and protein kinase C (PKC). [53] A proline-tyrosine (PY) motif present in the linker region of most R-Smads and I-Smads enables Smad interaction with the WW domains of the E3 ubiquitin ligases Smurf1 and Smurf2 (Smad ubiquitination-related factors) and SCF/Roc1 enabling ubiquitin-mediated proteasomal degradation. [54],[55] Smad4 linker region also includes a nuclear export signal (NES) [56] and a Smad4 activation domain that is required in transcriptional complexes, mediating the activation of Smad-dependent target genes. [4] Thus, phosphorylation of the Smads not only causes their activation but also modulates their activity and provides a mechanism for integration of the Smad pathway with other signaling pathways that can modulate TGF-β signaling. Mechanism of Smad Nucleo-Cytoplasmic Shuttling Basal state At the basal level, all R-Smads, mammalian Smad4 and Xenopus Smad4α reside in the cytoplasm. In contrast, Xenopus Smad4β and I-Smads localize to the cell nucleus. [27],[32],[49],[57] Smad4 constitutively shuttles between the cytoplasm and the nucleus, and its predominant cytoplasmic localization in unstimulated cells is due to active nuclear export mediated by a unique leucine-rich NES located in its linker region. Smad4 is continuously exported out of the nucleus by chromosome region maintenance 1 (CRM-1). Although the nuclear entry of Smad4 is a spontaneous event not requiring TGF-β signaling, CRM-1-mediated nuclear export must be suppressed by TGF-β in order to retain Smad4 in the nucleus. Smad4 therefore continuously shuttles in and out of the nucleus, and its oligomerization with R-Smads might occur en route to the nucleus. [56],[59],[60] C-terminal phosphorylation of Smad3 results in a conformational change that exposes the NLS for importinα1-dependent Ran-mediated nuclear import. [59],[61] Smad2, however, translocates into the nucleus by a cytosolic factor-independent import activity. This difference in the pathway taken up by two R-Smads is due to the presence of the unique exon 3 in the MH1 domain of Smad2. [59] Many of the previous studies have even suggested an importin-independent nuclear import mechanism for unphosphorylated Smad2, Smad3 and Smad4. Such a mechanism relies on the ability of Smad2, Smad3 and Smad4 to directly interact with phenylalanineglycine (FG) repeat-containing nucleoporins, including CAN/Nup214 and Nup153. [62],[63] Activated state In the activated state, counteracting nuclear import and export forces control the subcellular localization of Smad4. Because TGF-β stimulation does not noticeably accelerate nuclear import of Smad4, it most likely acts upon the CRM-1-mediated export to promote Smad4 accumulation in the nucleus. DNA binding cannot block, but instead promotes, CRM-1 association with Smad4. [64] Therefore, it is heterotrimerization that may cause physical occlusion of the CRM-1-binding site or may induce long-range conformational changes in Smad4, making it incapable of recognizing CRM-1. This Smad4 heterotrimeric complex stays in the nucleus until its dissociation is triggered by dephosphorylation of Smad2 and Smad3, resulting in its nuclear export by CRM-1. [65] Transcriptional Regulation of Target Genes by Smads Smad binding elements The Smad4 heterodimeric complex recognizes and binds to Smad Binding Elements (SBEs) present in the promoter sequences of various cell cycle regulatory genes. [30] SBE comprises of an 8 bp pallindromic sequence GTCTAGAC [66] or multiple copies of GTCT or AGAC. [67] While, full-length Smad4 protein can bind as such to SBE, binding by Smad3 to DNA requires either C-terminal phosphorylation or C-terminal truncation of the MH2 domain, both of which would release the inhibition of its MH1 domain. [68] The crystal structure analysis revealed a b-hairpin loop in Smad3 responsible for its direct DNA contact. The β-hairpin loop is conserved among R-Smads and Co-Smad. [69] Smad3 and Smad4 have also been reported to bind to GC-rich sequences. [70] Smad2, however, lacks the ability to bind DNA because of the presence of a small exon upstream of the b-hairpin, which when removed, confers DNA-binding ability to Smad2. [71],[72] The SBE AGAC sequence is calculated to be present on average once every 1024 bp in the genome, or about once in the regulatory region of any average size gene. If binding to the SBE were sufficient for Smad-dependent transcriptional activation, an activated Smad protein would lead to the nonselective activation of massive numbers of genes. However, activation of target genes solely via a SBE is not feasible for two reasons. Firstly, the affinity of a Smad MH1 domain for the SBE is in the 10 -7 M range, [69] which is too weak for effective binding in vivo without the involvement of additional transcriptional cofactors. This is supported by the fact that it takes many SBEs to achieve Smad activation of a reporter gene in artificial concatemers. [66] Secondly, Smad binding to the SBE lacks selectivity, as Smads 1, 3 and 4 have a similar affinity for the SBE. This is not surprising because the β-hairpin sequence is identical in all R-Smads and is highly conserved in Smad4. Therefore, additional transcriptional cofactors appear necessary for specific, high-affinity binding of a Smad complex to a target gene. TGF-β/Smad4 Signaling in Pancreatic Cancer Transforming growth factor-beta All three mammalian Transforming growth factor-beta (TGF-β) isoforms are overexpressed in pancreatic ductal adenocarcinoma (PDAC), and overexpression has been found to corDPC4relate with decreased patient survival. [73],[74] This is surprising, considering the negative regulatory effect of TGF-β on epithelial cell growth. Cancer cells probably lose the ability to respond to the growth inhibitory signals of TGF-β. The inactivating mutations in the Smad4 gene and upregulation of the inhibitory Smad6 and Smad7 genes have been found in many pancreatic cancers in which they inhibit TGF-β signaling. [10],[76] This was shown in pancreatic cancer cells that were resistant to TGF-β signaling despite high levels of TGF-β receptors, TβRI and TβRII. In pancreatic cancers, TGF-β deregulation, besides losing its ability to bring about growth suppression, promotes metastasis and brings about Epithelial Mesenchymal Transition (EMT). Smad4 downregulation counteracted TGF-β-induced cell cycle arrest and migration but not EMT, which results in increased motility and invasion. [77] There are some alternative TGF-β pathways, independent of Smad4, which contribute towards its metastatic role in transformed cells. Oncogenic K-ras has been shown to facilitate TGF-β-induced transcriptional downregulation of the tumor suppressor PTEN in a SMAD4-independent manner, and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers. [78] The contribution of TGF-β toward enhanced cancer progression can also be through its positive regulation of certain stromal elements, like membrane type 1-matrix metalloproteinase (MT1-MMP). [79] TGF-β suppresses PTEN in pancreatic cancer cells through NF-kappa B activation and enhances cell motility and invasiveness in a Smad4-independent manner that can be counteracted when TGF-β-Smad4 signaling is restored. The TGF-β/NF-kappaB/PTEN may be a critical pathway for pancreatic cancer cells to proliferate and metastasize. [80] Loss of Smad4, leading to aberrant activation of Stat3, contributes to the switch of TGF-βeta from a tumor-suppressive to a tumor-promoting pathway in pancreatic cancer. [81] The TGF-β/PKC/α -PTEN is yet another pathway implicating the change in the role of TGF-β signaling to a metastatic one. [82] In case where TGF-β is overexpressed, its inhibition by TbRI inhibitor reduced primary tumor growth and decreased the incidence of metastasis. [83],[84] A recent role identified for defective TGF-β signaling and can be utilized for future therapies is that it selectively sensitizes the pancreatic as well as colon cancers to rapamycin or other drugs targeting mTOR. [85] TGF-beta Receptors Reduced expression or inactivation of TGF-β receptors often correlates with malignant progression and loss of sensitivity to the antiproliferative effects of TGF-β. [86],[87] There are only sporadic reports of mutations or deletions in TβRI in malignancy. [88] A study showed that the individuals with constitutively decreased TβR1 expression may have a decreased risk of pancreatic cancer. [88] TβRII is a frequent locus of inactivating mutations, which may be because of a deficient DNA mismatch repair system. In one such case, frameshift mutations in a 10-basepair polyadenine tract (big polyadenine tract [BAT]) in exon 3 of the TβRII gene (BAT-RII) resulted in the production of truncated receptors where the serine-threonine kinase domain was absent. [86],[89] Repression of TGF-β receptor expression is a common mechanism that enables tumor cells to escape from negative regulation of growth by TGF-β. [90] Smad4 Although lost in many cancers, loss of Smad4 is more sensitive and specific to pancreatic cancer. [91] Studies have shown SMAD4 to be inactivated in 55% of pancreatic cancers. [10],[92],[93] The inactivation of SMAD4 gene occurs either by deletion of both alleles (35%) or by intragenic mutation in one allele coupled with the loss of the other allele (20%). [94] The mutations are often found in the C-terminal MH2 domain, which harbors a mutational hotspot corresponding to codons 330-370, termed as mutation cluster region (MCR). [95] The mutant protein cannot be recruited to DNA by transcription factors and hence cannot form transcriptionally active DNA-binding complexes. C-terminal truncation leads to decreased stability and prevents Smad4 homomeric complex formation and heteromeric complex formation with activated Smad2. Molecular modeling indicates that the truncation removes residues critical for homomeric and heteromeric Smad complex formation. [96] Another alternative route that the mutated Smad4 proteins may take is ubiquitin-proteosome degradation. [97] Deletion of Smad4 occurs at a later stage of Pan IN. [98] Loss of Smad4 protein expression highly correlated with the presence of widespread metastasis but not with locally destructive tumors. [99] Involvement of K-ras/ERK pathway, PTEN and RON, respectively, are implicated in the gain of metastatic potential of pancreatic cancers in the absence of Smad4. [81],[82],[100] Smad4 is thought to be dispensable for normal pancreas but critical for the progression of tumors with mutated K-ras gene. [101] Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGF-β-induced transcriptional downregulation of the tumor suppressor PTEN in a Smad4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers. SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas. [102],[103] Determination of Smad4 status at initial diagnosis may be of value in determining the stage and metastatic status of disease and will help in stratifying patients into treatment regimens accordingly. [104],[105] Success with SMAD4 gene transfection of Smad4-deficient cell lines has been variable. Introduction of Smad4 in BxPC3 cells with Smad4 homozygous deletion inhibited cell proliferation, but this effect was transient, indicating that Smad4 growth inhibitory actions were circumvented in the later stages of pancreatic tumorigenicity. [105] However, a recent gene transfection with SMAD4, using retroviral vector pLXSN, inhibited prolifertion in pancreatic cancer cell line. [106] Utilizing the loss of Smad4, some novel molecules (UA62001, UA62784) that specifically target and inhibit Smad4-deficient cancer cells have been discovered. [107],[108] Inhibitory Smads Previous studies have shown Smad7 overexpression in pancreatic cancer cell lines. [109],[110],[111] A recent study in patient samples, however, contradicts these results and shows a low expression of Smad7 in pancreatic cancer patients. The authors have demonstrated a significant correlation between low-Smad7 expression with lymph node metastasis and poor prognosis. [112] Different studies have isolated different molecules, like KLF11, retinoblastoma and thioredoxin, which are involved in Smad7-dependent aggressiveness of pancreatic cancer. [111],[113],[114] There are not many reports on Smad6 expression in pancreatic cancer. Smad6, along with Smad7 expression, was found to be elevated in a pancreatic cancer cell line. [109] One report on pancreatic cancer patient samples, however, contradicts this and demonstrates that the increased expression of Smad6 and Smad7 are infrequent in tumor compared with normal tissues. [115] The variation in the observed expression of two inhibitory Smads in cell lines as compared with the tissue samples can be because of a possible reversal of phenotype in artificial tissue culture systems. R-Smads There are not many reports regarding the role of R-Smads in pancreatic cancer. Smad2 mRNA levels were significantly increased in pancreatic cancer samples in comparison with normal pancreatic tissues. Authors suggest that this might lead to excessive activation of specific components of the TGF-beta-signaling pathway. [109] A missense mutation in an arginine residue of the MH1 domain of Smad2 was identified in pancreatic tissue samples from multiple patients. Although this alteration did not interfere with the majority of the Smad's cellular functions, it directed the Smad protein for degradation via the UbcH5 family of E2 ubiquitin ligases. Similar results were also found with mutations in the MH2 domain. This resulted in the disruption of the steady state kinetics of R-Smads due to amino acid substitutions, making cells resistant to the suppressive effects of TGF-β. [97] References
Copyright 2011 - Indian Journal of Cancer The following images related to this document are available:Photo images[cn11091f4.jpg] [cn11091f5.jpg] [cn11091f3.jpg] [cn11091f2.jpg] [cn11091f1.jpg] |
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