On the origin of cancer-associated fibroblasts

[Cell Cycle 8:10, 1461-1465; 15 May 2009]; ©2009 Landes Bioscience

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On the origin of cancer-associated fibroblasts Charlotte Anderberg and Kristian Pietras* Department of Medical Biochemistry and Biophysics; Division of Matrix Biology; Karolinska Institutet; Stockholm, Sweden

*Correspondence to: Kristian Pietras; Department of Medical Biochemistry and Biophysics; Division of Matrix Biology; Karolinska Institutet; House A3, level 4; Scheeles Väg 2; Stockholm SE-171 77 Sweden; Email: Kristian. [email protected] Submitted: 03/19/09; Accepted: 03/25/09 Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/8557

Malignant cells do not act as separate entities; they exist in the context of a rich microenvironment consisting of several different cell types and the extracellular matrix. The tumor cells and the microenvironment communicate extensively creating a complex and intricate signaling network aimed at promoting cancer initiation, progression and growth.1,2 The cancer-associated fibroblast (CAF) is the most prominent cell type in the tumor stroma.1,3 The widest definition of CAFs is all fibroblast cells within the tumor stroma, regardless of expression of myofibroblastic markers.4 Morphologically CAFs are identified as large cells with an elongated spindle shape.1,4,5 Fibroblasts in non-cancerous tissues are a heterogeneous population of cells expressing several different markers, none of which identify all varieties of fibroblasts, and few of which are exclusive to fibroblasts.3 Sugimoto and colleagues identified several subpopulations of CAFs with varying overlap of expression of markers such as fibroblast specific protein (FSP)-1, α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF) receptor-β and NG2.6 However, some of the markers used also label pericytes, and thus not all subpopulations described may represent CAFs. Nevertheless, the study demonstrates that the apparent heterogeneity is large also among CAFs, and no marker has so far been described as common to all CAF subtypes. In addition, it is still unclear whether the different types of CAFs harbor different functional properties with regard to promotion of tumor growth. CAFs have been shown to originate from at least four different compartments. Firstly, resident fibroblasts are the most immediate source for the recruitment of CAFs.4 Additionally, various cell types within the tumor, such as epithelial and endothelial cells, may transdifferentiate into mesenchymal cells.5,7 Also other mesenchymal cell types within the tumor, such as vascular smooth muscle cells, pericytes or adipocytes, could conceivably transdifferentiate into CAFs, although experimental evidence for such processes is still largely lacking. Moreover, CAFs may also be recruited from remote sources, e.g., bone-marrow derived precursors and mesenchymal stem cells have been described as a supply for CAFs.8-10 Common to all studies

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of the origin of CAFs in mouse tumors is that only a portion of the CAFs was found to be of a single origin, suggesting that all CAFs are not derived from the same source, but rather originate from several different supplies. Evidence from human tumors is scarce regarding the source(s) from which CAFs are recruited. We recently identified a role for PDGF-CC in the recruitment of CAFs into a syngeneic mouse model of melanoma.11 PDGF-C expression by tumor cells resulted in the recruitment of PDGF receptor-α expressing fibroblasts harboring a tumor growth-promoting phenotype denoted by the expression of the pro-survival and pro-angiogenic protein osteopontin. The recruited fibroblasts were found to be of different subclasses, as defined by differential expression of PDGF receptor-α, FSP-1 and α-SMA. All subsets of CAFs expressed α-SMA to varying degrees. The surrounding fibrotic capsule and sub-capsule area were populated by fibroblasts either displaying high and exclusive expression of PDGF receptor-α, or with lower expression of PDGF receptor-α accompanied by expression of FSP-1. Interestingly, in the tumor center a fibroblast subset expressing FSP-1, but with no discernible expression of PDGF receptor-α, was prevalent. Thus, despite the fact that the CAFs were specifically recruited into the tumor by PDGF-CC signaling through PDGF receptor-α, not all subsets of fibroblasts retained the expression of PDGF receptor-α at the time of analysis. Based on this observation, we propose a mechanism whereby PDGF-CC recruits, from local and/or remote sources, a CAF precursor population with high expression of PDGF receptor-α. Subsequently, these cells are educated by the tumor microenvironment into becoming mature and activated fibroblasts expressing activation markers, such as FSP-1 and α-SMA. In our studies of mouse melanoma, the effector protein osteopontin was secreted by CAFs expressing FSP-1, but with diminished expression of PDGF receptor-α, substantiating the proposition that even though signaling by PDGF receptor-α serves to recruit CAFs into tumors, it is not highly expressed by the fully competent CAFs. To corroborate the existence of discrete subpopulations of fibroblasts within tumors, we analyzed the differential expression of PDGF receptor-α, FSP-1 and α-SMA by CAFs in tumors from the K14-HPV16 mouse model of squamous cell carcinoma of the cervix.12 Indeed, as shown in Figure 1A, the cervical tumors were invested with different subsets of CAFs, based on their marker expression. To find evidence for the presence of different types of CAFs in human tumors, we mined the publicly available database the Human Protein Atlas (www.proteinatlas.org).13 The information provided in the database does not allow conclusions on the co-expression of different markers in cells within the same tissue section. Nevertheless, similar to the mouse model, the expression patterns of the CAF markers PDGF receptor-α, FSP-1 and α-SMA in human cervical carcinoma were only partially overlapping within the stromal compartment, and no marker consistently labeled all CAFs within the tumor, indicative of the occurrence of discrete subsets of stromal fibroblasts (Fig. 1B). CAFs appear to constitute a heterogenous population of cells. The evidence collected to date suggests that stromal fibroblasts in tumors are recruited from multiple different sources. Also, it is likely that CAFs within tumors of different origin display both common and site-specific properties, depending on the prevalent microenvironment. As a rich source of tumor growth-promoting factors, CAFs represent a highly interesting target for the development of therapeutic modalities.14 Such efforts should be facilitated by the identification of common markers for CAFs, as well as by more in-depth studies of the phenotypic conversion of normal, or precursor, fibroblasts into fully competent culprits of the disease.

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Convergent pathways link the endothelin A receptor to the β-catenin The β-arrestin connection Laura Rosanò and Anna Bagnato* Figure 1. Differential expression of markers by CAFs in mouse and human squamous cell carcinoma of the cervix. (A) Immunostaining for PDGF receptor-α (red) and FSP-1 (green) (left) or PDGF receptor-α (red) and α-SMA (green) (right) of sections from cervical squamous cell carcinomas from 5 months old K14-HPV16 mice. Arrows denote double positive cells, stars denote cells expressing only PDGF receptor-α, and arrowheads denote cells expressing only FSP-1 or α-SMA, respectively. (B) Immunostaining for PDGF receptor-α (left), FSP-1 (middle) and α-SMA (right) of sections from human squamous cell carcinomas of the cervix publicly available in the Human Protein Atlas database (www.proteinatlas.org). Images shown are representative examples from the database. Dotted line marks tumorstroma interface; T, tumor tissue; S, stromal tissue.

Acknowledgements K.P. is supported by grants from the Swedish Research Council, the Swedish Cancer Society and the Karolinska Institutet cancer research network.

References

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

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Micke P, et al. Expert Opin Ther Targets 2005; 9:1217-33. Kunz-Schughart LA, et al. Histol Histopathol 2002; 17:623-37. Kunz-Schughart LA, et al. Histol Histopathol 2002; 17:599-621. Micke P, et al. Lung Cancer 2004; 45:163-75. Kalluri R, et al. Nat Rev Cancer 2006; 6:392-401. Sugimoto H, et al. Cancer Biol Ther 2006; 5:1640-6. Zeisberg EM, et al. Cancer Res 2007; 67:10123-8. Karnoub AE, et al. Nature 2007; 449:557-63. Ishii G, et al. Int J Cancer 2005; 117:212-20. Sangai T, et al. Int J Cancer 2005; 115:885-92. Anderberg C, et al. Cancer Res 2009; 69:369-78. Arbeit JM, et al. Proc Natl Acad Sci USA 1996; 93:2930-5. Ponten F, et al. J Pathol 2008; 216:387-93. Pietras K, et al. PLoS Med 2008; 5:19.

Molecular Pathology Laboratory; Regina Elena Cancer Institute; Rome, Italy

*Correspondence to: Anna Bagnato; Regina Elena Cancer Institute; Via delle Messi D’Oro 156; Rome 00158 Italy; Tel.: 39.06.52662565; Fax: 39.06.52662600; Email: [email protected] Submitted: 03/19/09; Accepted: 03/25/09 Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/8559

Metastatic relapses remain a major challenge in the management of ovarian cancer.1 Accumulating evidence suggest that the activation of the G-protein coupled receptor (GPCR) endothelin A receptor (ETAR) by endothelin-1 (ET-1) has a critical role in ovarian tumorigenesis by promoting different functions, including cell proliferation, survival, migration, neovascularization and epithelial-to-mesenchymal transition (EMT),2,3 an event characterized by stabilization of β-catenin.4,5 How the interplay between ETAR and β-catenin signaling leads to ovarian cancer progression remains poorly understood. Here we describe the functional interaction between the ETAR and β-catenin pathways that occurred through several coordinated mechanisms. As previously reported, ETAR-mediated activation of PI3K/integrin-linked kinase (ILK)/AKT contributes to promotes β-catenin stabilization through inactivation of glycogen synthase kinase-3β (GSK-3β). This inactivation leads to the stabilization and nuclear translocation of β-catenin where it interacts with T-cell factor/lymphoid enhancer factor (TCF/LEF) to activate transcription of genes involved in EMT.6,7 However, these ETAR-generating systems alone may not able to explain the diversity of effects stimulated by ET-1 through ETAR. The various functions of GPCR are often mediated by the ability of β-arrestin to serve as a signal transducer and scaffold molecule, bringing elements of diverse signaling pathways into proximity thereby facilitating their activation, which lead to MAPK activation, DNA synthesis, protein translation and cell migration.8-11 This new paradigm for understanding the unrecognized signaling properties of the β-arrestin has been recently explored in our laboratory using ovarian cancer cells expressing endogenous levels of ETAR.12 In ovarian cancer cells upon ET-1 stimulation, β-arrestin is recruited to ETAR to form a trimeric complex with Src. The association of ETAR/β-arrestin/c-Src signaling complex or “signalplex” leads to epidermal growth factor receptor (EGFR) transactivation and downstream activation of AKT and MAPK. This signalplex formation is also required for ET-1-induced β-catenin tyrosine phosphorylation,

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Figure 1. A summary of the pathways leading to β-catenin induction by ET-1/ETAR axis. Binding of ET-1 to ETAR in ovarian cancer leads to the recruitment of β-arrestin to the activated receptor. (1) As a signal transducer, β-arrestin mediates the ETAR-activated PI3K-ILK-Akt signaling route, which causes the phosphorylation and inactivation of GSK-3β, thus leading to accumulation of a non-Ser/Thr phosphorylated, active β-catenin. (2) Concomitantly, ETAR/β-arrestin associates with c-Src, which initiates the transactivation of the EGFR and subsequent the tyrosine phosphorylation of β-catenin, contributing to accumulation of an active form of β-catenin. (3) In a paralleled and coordinated mechanism ETAR/β-arrestin complex binds axin, thereby promoting the release of GSK-3β from the complex and its inactivation. Finally, free β-catenin enters the nucleus and forms a transcription complex with TCF/LEF, involved in the expression of metastasispromoting genes.

thereby mobilizing the fraction of β-catenin associated to E-cadherin and increasing its free cytosolic pool. Cells which overespress mutant β-arrestin (S412D), which has been shown to inhibit c-Src binding, or cells depleted of either β-arrestin, exhibited decreased tyrosine phosphorylated β-catenin, indicating the critical role of β-arrestin-driven signalplex formation in EGFR-mediated β-catenin tyrosine phosphorylation induced by ET-1. ETAR-promoted tyrosine phosphorylated β-catenin binds TCF4 in nuclear extracts promoting activation of target genes. To underscore the complexity of the mechanisms available to ETAR to interlink β-catenin pathways highlighting the importance of β-arrestins as signal transducers,13,14 we explored whether β-arrestin may also provide a link between ETAR and axin. We demonstrate that β-arrestin is recruited to ETAR to form a complex through the physical association with axin, contributing through a parallel and coordinated mechanism to release and inactivate GSK-3β and to stabilize β-catenin. Thus, ET-1-induced binding of β-arrestin to axin is required to induce the displacement of GSK-3β from axin-containing complex and its functional inhibition. Based on these results, we also observed that ETAR-mediated activation of PI3K/ILK/AKT-driven inactivation of GSK-3β was impaired in β-arrestin-1-silenced cells, confirming the function of β-arrestin as signal transducer in ETAR-mediated β-catenin signaling (Rosanò L et al., unpublished data).


Altogether, these results strongly imply that the ETAR signals through β-arrestin as an integral component of at least two trimeric functional complexes involved in β-catenin signaling, one consisting of ETAR, β-arrestin and Src that controls cross-talk with the EGFR, and another with axin which mediates signaling to GSK-3β (Fig. 1). Moreover ETAR/β-arrestin could also mimic the canonical Wnt signaling to inactivate GSK-3β via AKT through PI3K/ILK, resulting in the stabilization and nuclear translocation of β-catenin. In the nucleus β-catenin interacts with cofactor TCF and LEF to activate transcription of genes that promote ovarian cancer cell invasion. Interestingly β-arrestin-silenced cells exhibits decreased cellular invasion and cells which overespress mutant β-arrestin-1 S412D show reduced metastatic ability compared to the control, implicating a functional role for β-arrestin as a mediator of cellular invasion and metastasis. In the metastatic nodules derived from cells expressing S412D-β-arrestin mutant the expression of active β-catenin was strongly inhibited, further supporting that the ETAR-dependent β-catenin pathway is involved in the invasive and metastatic properties of ovarian cancer cell in vivo in a β-arrestindependent manner. The present results, together with the observation that the co-expression of ETAR and β-arrestin may be indicative of a more aggressive phenotypes of primary human ovarian cancers, reveal a molecular map showing that the recruitment of β-arrestin to ETAR may represent a check-point controlling multiple pathways converging on β-catenin signaling to promote invasion and metastasis. A detailed understanding of the molecular mechanisms that control ovarian cancer metastasis is a crucial step in identifying new effective therapies.15 The recent preclinical demonstration of tumor growth inhibition,16,17 together with reduced metastatic potential in response to ZD4054, a specific ETAR antagonist, suggest that this treatment, by simultaneously disabling multiple intertwined circuits activated by ETAR in a β-arrestin-dependent manner, provide a molecular framework for the development of pathway-specific therapeutics for ovarian cancer. Although these findings reveal the interconnected signals fully engaged in the interplay between ETAR and β-catenin signaling, several questions still remain. For example, is there a role of β-arrestin as a nuclear scaffolding protein to mediate epigenetic signaling modulating β-catenin trancription? This and other issues are currently being addressed to understand the early events leading to the progression of ovarian cancer, characterized by a highly aggressive biological behavior.

References

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

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Jemal A, et al. CA Cancer J Clin 2006; 56:4-5. Nelson J, et al. Nat Rev Cancer 2003; 3:110-6. Bagnato A, et al. Endocr Relat Cancer 2005; 12:761-72. Thiery J, et al. Nat Rev Mol Cell Biol 2006; 7:131-42. Tse JC, et al. J Cell Biochem 2007; 101:816-29. Rosanò L, et al. Cancer Res 2005; 65:11649-57. Rosanò L, et al. Mol Cancer Ther 2006; 5:833-42. Luttrell LM, et al. Proc Natl Acad Sci USA 2001; 98:2449-54. Lin FT, et al. J Biol Chem 1998; 273:31640-3. DeWire SM, et al. J Biol Chem 2008; 283:10611-20. Buchanan FG, et al. Proc Natl Acad Sci USA 2006; 103:1492-7. Rosanò L, et al. Proc Natl Acad Sci USA 2009; 106:2806-11. Chen W, et al. Proc Natl Acad Sci USA 2001; 98:14889-94. Bryja V, et al. Proc Natl Acad Sci USA 2007; 104:6690-5. Naora H, et al. Nat Rev Cancer 2005; 5:355-66. Rosanò L. Mol Cancer Ther 2007; 6:2003-11. Rosanò L, et al. Cancer Res 2007; 67:6351-9.

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IRF9. This complex activates genes comprising an ISRE (IFN Stimulated Responsive Element) DNA motif. Fine-tuning of the transcriptional outcome in response to IFN stimulation is achieved by a variety of coregulators, including kinases, phosphatases, acetylases, SOCS proteins and the PIAS protein family. The nuclear protein PIAS1 acts as an inhibitor of STAT1-dependent transcription by it’s ability to bind STAT1 dimers. This interaction results in a diminished DNA binding capacity of STAT1.3 Studies in PIAS1 knock-out mice demonstrated that PIAS1 inhibits a specific subset of STAT1 target genes in response to IFN stimulation. Interestingly, the PIAS1-regulated subset of genes harbors imperfect (low-affinity) GAS sites in the promoters suggesting that the suppression of STAT1 DNA binding by PIAS1 does not affect high-affinity binding sites.4


Arginine methylation in interferon signaling New light on an old story Susanne Weber and Uta-Maria Bauer* Institute of Molecular Biology and Tumor Research (IMT); Philipps University of Marburg; Marburg, Germany

Key words: arginine methylation, PRMT1, PIAS1, STAT1, IFN signaling, JAK-STAT pathway *Correspondence to: Uta-Maria Bauer; Institut für Molekularbiologie und Tumorforschung; Philipps-Universität Marburg; Emil-Mannkopff-Str. 2; Marburg 35033 Germany; Email: [email protected] Submitted: 03/19/09; Accepted: 03/25/09 Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/8560

Interferons (IFNs) are key regulators of the innate and adaptive immune system implicated in viral and bacterial host defence. Their capacity to modulate proliferation, apoptosis and cell survival in normal as well as tumor cells renders them an interesting target for cancer therapy. Within the past 50 years tremendous efforts have been made to determine the underlying IFN signal transduction pathways and to elucidate the biological function of interferon stimulated genes (ISGs). Since the JAK-STAT pathway has been clarified to be the major signal transduction pathway in response to IFN stimulation, a variety of posttranslational modifications that regulate this pathway have been identified and characterized. The role of arginine methylation was under discussion. Recent data shed light on this topic by the identification of a single arginine methylation site in the transcriptional inhibitor PIAS1 (Protein Inhibitor of Activated STAT1), which is targeted by PRMT1 (Protein Arginin Methyltransferase 1) in the late phase of the IFNγ response. We show here that PIAS1 methylation is also implicated in IFNα signaling.

Inhibition of the JAK-STAT Pathway by PIAS1 Activation of the JAK-STAT pathway is triggered by the binding of IFNs to their cognate cell surface receptors, finally resulting in the tyrosine phoshorylation of STAT (Signal Transducer and Activator of Transcription) transcription factors. In response to IFNγ STAT1 homodimerizes via a reciprocal phosphotyrosine-SH2 interaction. This dimerization yields in exposure of a nuclear localization sequence (NLS) and in shuttling of STAT1 to the nucleus. Activated nuclear STAT1 dimers are recruited to specific DNA sequences, the gamma acivated sites (GAS), thereby inducing the transcription of ISGs.1,2 In contrast, IFNα stimulation predominantly results in the assembly of the transcriptional active ISGF3 complex consisting of STAT1, STAT2 and

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The Role of PRMT1 and Arginine Methylation in JAK-STAT Signaling In the last years several reports revealed that arginine methylation regulates IFN signaling. The first indication came from an article reporting an interaction between PRMT1 and the cytoplasmic domain of the IFNα receptor.5 A PRMT1-mediated methylation of STAT1, which was observed mainly based on the use of methylation specific antibodies and methyltransferase inhibitors,6 could not be confirmed by others.7,8 Further, the commonly used methyltransferase inhibitor MTA executes strong site-effects on cellular kinases and importantly on the activation of STAT1 itself.8 Recent studies of our group established a novel mechanism how arginine methylation by PRMT1 regulates IFN signaling.9 We found that siRNA-mediated depletion of PRMT1 results in a hyperactivation of a subset of STAT1 target genes, which are similarly regulated by PIAS1. Subsequently, we discovered that PRMT1 methylates PIAS1 at arginine 303 (R303) in the late phase of the IFNγ response and that this methylation is necessary for PIAS1-mediated transcriptional repression. Mechanistically this methylation promotes the interaction of PIAS1 with STAT1 dimers and thereby facilitates inhibition of STAT1dependent transcription. Our study uncovered that the PIAS1 protein acts on the chromatin level. With the help of PIAS1 R303 mutants we demonstrated that methylation of PIAS1 is a prerequisite for its recruitment to STAT1 target gene promoters. These findings lead to the conclusion that the PIAS1-regulated subset of target genes is on the one hand defined by the characteristics of their GAS sites and on the other hand by the repressive activity of PRMT1. As PRMT1 associates with STAT1 target gene promoters independently of PIAS1, it is possible that PRMT1 attracts PIAS1 to the chromatin, thereby modulating target gene selection. Here we show that PIAS1 methylation is also important for IFNα signaling, as siRNA-mediated depletion of PIAS1 and PRMT1 results in an increased transcriptional activation of the IFNα target genes CXCL10 and IL6 (Fig. 1A). Similar to the IFNγ response, PIAS1 regulates only a subset of genes upon IFNα stimulation as the IRF1 gene is not influenced by the knockdown of neither PRMT1 nor PIAS1 (Fig. 1A). Furthermore, we find that the methylation-deficient PIAS1 R303K mutant is unable to properly inhibit transcriptional activation of PIAS1regulated genes, while the methylation-mimicking R303F mutant is capable (Fig. 1B). This suggests that R303 methylation of PIAS1 also regulates the IFN response triggered by the ISGF3 complex. The proposed mechanism of arginine methylation-dependent PIAS1-mediated shut-down or restriction of IFN signaling is summarized in Figure 1C, underlining the specificity of target gene selection and thereby the fine-tuning of the IFN response.

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or STAT1. Additionally, the chromatin function of PIAS1 should be further analyzed to clarify how the inhibition of STAT1 by PIAS1 works mechanistically.

Acknowledgements This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG).

References

1. Levy DE, et al. Nat Rev Mol Cell Biol 2002; 3:651-62. 2. Borden EC, et al. Nat Rev Drug Discov 2007; 6:975-90. 3. Liu B, et al. Proc Natl Acad Sci USA 1998; 95:10626-31. 4. Liu B, et al. Nat Immunol 2004; 5:891-8. 5. Abramovich C, et al. EMBO J 1997; 16:260-6. 6. Mowen KA, et al. Cell 2001; 104:731-41. 7. Meissner T, et al. Cell 2004; 119:587-9. 8. Komyod W, et al. J Biol Chem 2005; 280:21700-5. 9. Weber S, et al. Genes Dev 2009; 23:118-32.

Figure 1. Methylation of PIAS1 regulates IFN type l and type ll signaling. (A) RTqPCR analysing target gene expression upon IFNα stimulation in PRMT1/PIAS1-depleted cells. HeLa cells were transiently transfected with siRNA against Luciferase (siLuciferase, control siRNA), PRMT1 (siPRMT1) or PIAS1 (siPIAS1). 48 hours post-transfection cells were stimulated with 5 U/ml IFNα. Subsequently RNA was harvested and analysed by RTqPCR. (B) HeLa cells were transiently transfected with control (mock) plasmid, pN3-PIAS1 WT (wild type), pN3-PIAS1 R303K (methylation-deficient) or pN3-PIAS1 R303F (methylation-mimicking). 48 hours post-transfection cells were stimulated with 5 U/ml IFNα and analysed as in (A). (C) Model for the negative regulation of the JAK-STAT pathway by PRMT1 and PIAS1. STAT1 homodimers or the ISGF3 complex are formed upon IFNγ and IFNα stimulation, respectively, which allows transcriptional activation of ISGs. In the course of the IFNγ as well as IFNα response, PRMT1-mediated methylation of PIAS1 is induced resulting in the recruitment of PIAS1 to a subset of STAT1 target gene promoters. This event triggers the shut-down of target gene transcription by suppression of STAT1 DNA binding.

Outlook IFNs exert their biological function mainly by inducing IFN stimulated genes (ISG). Although much is known about the main signaling components, the mechanisms of target gene selection in different cell types, the dependency on the IFN concentration and the restriction of the pathway are still under investigation. In future, it will be interesting to discover the factors/events that trigger activation of PRMT1 and allow IFN-induced arginine methylation of PIAS1, and to elucidate whether this methylation cross-talks with other modifications on PIAS1


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