- Email: [email protected]
Keeping Stem Cells in Check: A Hippo Balancing Act
Cell Stem Cell
Previews environment or are other master regulators of stress response pathways such as FoxO3a or p53 (Warr et al., 2011) also important in tailoring the metabolic makeup of self-renewing HSCs? Lastly, are mutations in Pdk2/4 or Ptpmt1 associated with blood diseases and do leukemia-initiating stem cells have changes in their metabolic wiring that would make them distinct from normal HSCs and could be amenable to therapeutic intervention? These are just a few of the myriad questions that are emerging from these two exciting works, which have brought us a step closer to understanding HSC stemness from the standpoint of regulation of energy supply and demand.
Suda, T., Takubo, K., and Semenza, G.L. (2011). Cell Stem Cell 9, 298–310.
REFERENCES Csaszar, E., Kirouac, D.C., Yu, M., Wang, W., Qiao, W., Cooke, M.P., Boitano, A.E., Ito, C., and Zandstra, P.W. (2012). Cell Stem Cell 10, 218–229. Folmes, C.D., Dzeja, P.P., Nelson, T.J., and Terzic, A. (2012). Cell Stem Cell 11, 596–606. Ito, K., Carracedo, A., Weiss, D., Arai, F., Ala, U., Avigan, D.E., Schafer, Z.T., Evans, R.M., Suda, T., Lee, C.H., and Pandolfi, P.P. (2012). Nat. Med. 18, 1350–1358.
Takubo, K., Nagamatsu, G., Kobayashi, C.I., Nakamura-Ishizu, A., Kobayashi, H., Ikeda, E., Goda, N., Rahimi, Y., Johnson, R.S., Soga, T., et al. (2013). Cell Stem Cell 12, this issue, 49–61. Takubo, K., Goda, N., Yamada, W., Iriuchishima, H., Ikeda, E., Kubota, Y., Shima, H., Johnson, R.S., Hirao, A., Suematsu, M., and Suda, T. (2010). Cell Stem Cell 7, 391–402.
Pietras, E.M., Warr, M.R., and Passegue´, E. (2011). J. Cell Biol. 195, 709–720.
Warr, M.R., Pietras, E.M., and Passegue´, E. (2011). Wiley Interdiscip Rev Syst Biol Med 3, 681–701.
Simsek, T., Kocabas, F., Zheng, J., Deberardinis, R.J., Mahmoud, A.I., Olson, E.N., Schneider, J.W., Zhang, C.C., and Sadek, H.A. (2010). Cell Stem Cell 7, 380–390.
Yu, W.-M., Liu, X., Shen, J., Jovanovic, O., Pohl, E.E., Gerson, S.L., Finkel, T., Broxmeyer, H.E., and Qu, C.-K. (2013). Cell Stem Cell 12, this issue, 62–74.
Keeping Stem Cells in Check: A Hippo Balancing Act Louis Vermeulen1,2,* 1Cancer
Research UK, Cambridge Research Institute, Cambridge CB2 0RE, UK for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1105 AZ Amsterdam, the Netherlands *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2012.12.004 2Laboratory
Knowing when to stop proliferation is crucial for any regenerative process. In a recent issue of Nature, Barry et al. (2012) report that the Hippo pathway component YAP negatively regulates Wnt signaling, thereby preventing stem cell overpopulation after a regenerative response in the intestine. During homeostasis a complex interplay of morphogenetic pathways preserve epithelial integrity in the gut. These pathways, which include Wnt and Notch signaling, maintain a functional stem cell pool and regulate differentiation processes. More recent data indicate that the same signaling cascades are crucial for proper tissue regeneration after injury of the adult intestine. For example, it has been demonstrated not only that Wnt signaling is critical for gut repair but also that artificial increase of Wnt activity, e.g., by infusion of the Wnt agonist R-spondin1, augments the efficacy of the regenerative response (Kim et al., 2005). In contrast to our rather extensive knowledge of pathways that regulate
stem cell properties in the intestine during homeostasis and tissue regeneration, only a very limited number of studies examine the mechanisms that keep stem cells in check after a regenerative response to prevent tissue overcrowding and dysplasia. An important player in this so-called ‘‘crowd control’’ mechanism is the Hippo pathway. This pathway, originally discovered in Drosophila, is most well known for its ability to regulate organ size (reviewed in Mauviel et al., 2012). When the Hippo cascade is active, the downstream effector of this pathway Yes-associated protein (YAP) is phosphorylated at S127 by the LATS1/2 kinases. Phosphorylated YAP remains in the cytoplasm and as such cannot exert its proproliferative and antiapoptotic
function in the nucleus, which is mainly mediated by its binding to TEAD1-4 transcription factors. In addition, cytoplasmic YAP can directly antagonize the Wnt pathway, thereby further contributing to the role of Hippo signaling in preventing proliferation and stem cell expansion (Konsavage and Yochum, 2012). The relevance of the Wnt antagonizing effects of YAP in controlling intestinal stem cell expansion after regeneration was recently uncovered in an elegant series of experiments performed in the Camargo laboratory (Barry et al., 2012). Barry et al. (2012) report that epithelialspecific overexpression of the YAP (S127A) mutant, which importantly is predominantly localized in the cytoplasm in this tissue, induces intestinal hypotrophy
Cell Stem Cell 12, January 3, 2013 ª2013 Elsevier Inc. 3
Cell Stem Cell
Previews
and loss of crypt base (Schlegelmilch et al., 2011). columnar stem cells. MechaThere are several possibilities nistically, YAP(S127A) exfor this contrasting phenotype pression results in abrogation including context-dependent of Wnt signaling in the intespathway interactions, differtine in vivo. In agreement ential roles of the Wnt pathwith previous reports, YAP way in either tissue, or subcelloss in the intestine only lular localization differences marginally affects intestinal of the YAP(S127A) mutant. homeostasis (Cai et al., While the biological differ2010); however, the effects ences underlying the discrepof YAP loss become signifiancy between the effects of cant when a Wnt-dependent YAP expression in the skin regenerative response is and the intestine are not yet induced either by g-irradiaentirely clear, in the gut itself tion or by adenovirus-medithe effects of YAP overexated R-spondin1 expression. pression are not unambigIn those cases, YAP loss uous either. In the current results in a rapid expansion study by Barry et al. (2012), of the intestinal stem cell epithelial cell-specific YAP compartment and forma(S127A) expression results in a degenerative phenotype; tion of ectopic crypt regions however, when the same YAP and even microadenomas, which is in fact a phenotype mutant is expressed using very reminiscent of intestinal a ubiquitous promoter, intesFigure 1. A Novel Crosstalk Mechanism between the Hippo and Wnt APC loss as observed in tinal dysplasia with expansion Pathways Active Hippo signaling results in phosphorylation of YAP by LATS1/2 kinases. the APCmin mouse model. of undifferentiated progenitor Phosphorylated YAP remains located in the cytoplasm. Cytosolic-located YAP These data indicate that cells is observed (Camargo interacts directly with Dishevelled (DVL) and inhibits its nuclear translocation. YAP is involved in controlling et al., 2007). These results Nuclear DVL activates, parallel to the canonical Wnt pathway, a Wnt expresthe activity of the Wnt pathare especially intriguing as it sion program. YAP is crucial to restrain a Wnt-related regenerative response. Note that nuclear YAP (orange) functions as an oncogene and induces tranway during regeneration and indicates that the Hippo pathscription of a proliferation-inducing and antiapoptotic gene expression thereby also preventing tisway mediates potent paraprogram. Cytosolic YAP (green) functions as a tumor suppressor by inhibiting sue hypertrophy and dyscrine effects of the intestinal the Wnt pathway. plasia. The precise mechastroma, a concept that is in nism by which this occurs is line with a recent study reportnot entirely resolved yet, although it is tutive activation of the Wnt pathway seen ing that YAP expression indeed has parasuggested by Barry et al. (2012) that it in the vast majority of colorectal cancers crine functions and promotes secretion of does not involve sequestering of b-cate- (CRCs). Consequently, the Wnt target the EGFR ligand amphiregulin (Zhang nin in the cytoplasm or inhibition of gene YAP is upregulated in many CRCs. et al., 2009). GSK3b function within the b-catenin Interestingly, Barry et al. (2012) now idenTo conclude, the current work suggests degradation complex, which are two pre- tify a small fraction of CRCs that show low that YAP is a tumor suppressor gene in viously reported mechanisms by which expression of YAP protein and that have CRC, as Barry et al. (2012) additionally cytosolic YAP negatively regulates a dismal prognosis. The mechanism by showed that patients with low YAP Wnt signaling (Konsavage and Yochum, which YAP expression is restricted in expression levels have a poor prognosis 2012). Instead, Barry et al. (2012) propose these patients is unclear, but it could and overexpression of YAP results in a novel mechanism in which cytoplasmic involve promoter methylation that is impaired subcutaneous tumor growth of YAP directly inhibits nuclear translocation also described to be responsible for de- the DLD-1 CRC cell line. Intriguingly, of Dishevelled proteins where it promotes creased expression of other negative these findings appear to be counterintuiWnt target gene expression, in a parallel regulators of the Wnt pathway. tive based on previous work. Two recent It should be noted that several of reports showed that shRNA-mediated manner to the canonical b-catenin mediated activity of this pathway (Figure 1). the findings by Barry et al. (2012) con- downregulation of YAP in a panel of In many respects, cancer can be trast with previous paradigms of YAP CRC cell lines inhibits colony formation perceived as a disease in which stem function that were established in the field. and subcutaneous tumor growth (Koncell proliferation is no longer restricted First of all, the effects of epithelial cell- savage et al., 2012; Zhou et al., 2011), and causes tissue overpopulation. This specific YAP overexpression in the intes- which would be inconsistent with a tumor is often a consequence of mutations tine are opposite to the effects of YAP suppressor role for YAP in the intestine. causing activation of pathways promoting overexpression in the skin where it One possibility for resolving these opposstem cell proliferation and self-renewal. A strongly promotes stem cell expansion ing findings can be reached by appreprime example of this notion is the consti- and results in thickening of the skin ciating the different functions YAP has 4 Cell Stem Cell 12, January 3, 2013 ª2013 Elsevier Inc.
Cell Stem Cell
Previews depending on its subcellular localization. In this respect, nuclear YAP is thought to function mainly as an oncogene and promotes proliferation and expression of antiapoptotic proteins, while cytoplasmic YAP is a typical tumor suppressor that downregulates the Wnt pathway. If this hypothesis is true, it will be a true challenge to appropriately target this molecule for clinical benefit. Clever strategies need to be developed that selectively inhibit the oncogenic properties of this protein while promoting the tumor suppressor functions. Potentially, this could be achieved by interfering with the YAP-TEAD interaction or by inhibiting its nuclear translocation. In any case, it will be interesting to follow how efforts to manipulate YAP function will develop.
REFERENCES Barry, E.R., Morikawa, T., Butler, B.L., Shrestha, K., de la Rosa, R., Yan, K.S., Fuchs, C.S., Magness, S.T., Smits, R., Ogino, S., et al. (2012). Nature. Published online November 25, 2012. http://dx.doi.org/10.1038/nature11693. Cai, J., Zhang, N., Zheng, Y., de Wilde, R.F., Maitra, A., and Pan, D. (2010). Genes Dev. 24, 2383–2388. Camargo, F.D., Gokhale, S., Johnnidis, J.B., Fu, D., Bell, G.W., Jaenisch, R., and Brummelkamp, T.R. (2007). Curr. Biol. 17, 2054–2060. Kim, K.A., Kakitani, M., Zhao, J., Oshima, T., Tang, T., Binnerts, M., Liu, Y., Boyle, B., Park, E., Emtage, P., et al. (2005). Science 309, 1256–1259. Konsavage, W.M., Jr., and Yochum, G.S. (2012). Acta Biochim Biophys Sin (Shanghai). Published online September 30, 2012. http://dx.doi.org/10. 1093/abbs/gms084.
Konsavage, W.M., Jr., Kyler, S.L., Rennoll, S.A., Jin, G., and Yochum, G.S. (2012). J. Biol. Chem. 287, 11730–11739. Mauviel, A., Nallet-Staub, F., and Varelas, X. (2012). Oncogene 31, 1743–1756. Schlegelmilch, K., Mohseni, M., Kirak, O., Pruszak, J., Rodriguez, J.R., Zhou, D., Kreger, B.T., Vasioukhin, V., Avruch, J., Brummelkamp, T.R., and Camargo, F.D. (2011). Cell 144, 782–795. Zhang, J., Ji, J.Y., Yu, M., Overholtzer, M., Smolen, G.A., Wang, R., Brugge, J.S., Dyson, N.J., and Haber, D.A. (2009). Nat. Cell Biol. 11, 1444–1450. Zhou, D., Zhang, Y., Wu, H., Barry, E., Yin, Y., Lawrence, E., Dawson, D., Willis, J.E., Markowitz, S.D., Camargo, F.D., and Avruch, J. (2011). Proc. Natl. Acad. Sci. USA 108, E1312– E1320.
Cell Stem Cell 12, January 3, 2013 ª2013 Elsevier Inc. 5
Previews environment or are other master regulators of stress response pathways such as FoxO3a or p53 (Warr et al., 2011) also important in tailoring the metabolic makeup of self-renewing HSCs? Lastly, are mutations in Pdk2/4 or Ptpmt1 associated with blood diseases and do leukemia-initiating stem cells have changes in their metabolic wiring that would make them distinct from normal HSCs and could be amenable to therapeutic intervention? These are just a few of the myriad questions that are emerging from these two exciting works, which have brought us a step closer to understanding HSC stemness from the standpoint of regulation of energy supply and demand.
Suda, T., Takubo, K., and Semenza, G.L. (2011). Cell Stem Cell 9, 298–310.
REFERENCES Csaszar, E., Kirouac, D.C., Yu, M., Wang, W., Qiao, W., Cooke, M.P., Boitano, A.E., Ito, C., and Zandstra, P.W. (2012). Cell Stem Cell 10, 218–229. Folmes, C.D., Dzeja, P.P., Nelson, T.J., and Terzic, A. (2012). Cell Stem Cell 11, 596–606. Ito, K., Carracedo, A., Weiss, D., Arai, F., Ala, U., Avigan, D.E., Schafer, Z.T., Evans, R.M., Suda, T., Lee, C.H., and Pandolfi, P.P. (2012). Nat. Med. 18, 1350–1358.
Takubo, K., Nagamatsu, G., Kobayashi, C.I., Nakamura-Ishizu, A., Kobayashi, H., Ikeda, E., Goda, N., Rahimi, Y., Johnson, R.S., Soga, T., et al. (2013). Cell Stem Cell 12, this issue, 49–61. Takubo, K., Goda, N., Yamada, W., Iriuchishima, H., Ikeda, E., Kubota, Y., Shima, H., Johnson, R.S., Hirao, A., Suematsu, M., and Suda, T. (2010). Cell Stem Cell 7, 391–402.
Pietras, E.M., Warr, M.R., and Passegue´, E. (2011). J. Cell Biol. 195, 709–720.
Warr, M.R., Pietras, E.M., and Passegue´, E. (2011). Wiley Interdiscip Rev Syst Biol Med 3, 681–701.
Simsek, T., Kocabas, F., Zheng, J., Deberardinis, R.J., Mahmoud, A.I., Olson, E.N., Schneider, J.W., Zhang, C.C., and Sadek, H.A. (2010). Cell Stem Cell 7, 380–390.
Yu, W.-M., Liu, X., Shen, J., Jovanovic, O., Pohl, E.E., Gerson, S.L., Finkel, T., Broxmeyer, H.E., and Qu, C.-K. (2013). Cell Stem Cell 12, this issue, 62–74.
Keeping Stem Cells in Check: A Hippo Balancing Act Louis Vermeulen1,2,* 1Cancer
Research UK, Cambridge Research Institute, Cambridge CB2 0RE, UK for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1105 AZ Amsterdam, the Netherlands *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2012.12.004 2Laboratory
Knowing when to stop proliferation is crucial for any regenerative process. In a recent issue of Nature, Barry et al. (2012) report that the Hippo pathway component YAP negatively regulates Wnt signaling, thereby preventing stem cell overpopulation after a regenerative response in the intestine. During homeostasis a complex interplay of morphogenetic pathways preserve epithelial integrity in the gut. These pathways, which include Wnt and Notch signaling, maintain a functional stem cell pool and regulate differentiation processes. More recent data indicate that the same signaling cascades are crucial for proper tissue regeneration after injury of the adult intestine. For example, it has been demonstrated not only that Wnt signaling is critical for gut repair but also that artificial increase of Wnt activity, e.g., by infusion of the Wnt agonist R-spondin1, augments the efficacy of the regenerative response (Kim et al., 2005). In contrast to our rather extensive knowledge of pathways that regulate
stem cell properties in the intestine during homeostasis and tissue regeneration, only a very limited number of studies examine the mechanisms that keep stem cells in check after a regenerative response to prevent tissue overcrowding and dysplasia. An important player in this so-called ‘‘crowd control’’ mechanism is the Hippo pathway. This pathway, originally discovered in Drosophila, is most well known for its ability to regulate organ size (reviewed in Mauviel et al., 2012). When the Hippo cascade is active, the downstream effector of this pathway Yes-associated protein (YAP) is phosphorylated at S127 by the LATS1/2 kinases. Phosphorylated YAP remains in the cytoplasm and as such cannot exert its proproliferative and antiapoptotic
function in the nucleus, which is mainly mediated by its binding to TEAD1-4 transcription factors. In addition, cytoplasmic YAP can directly antagonize the Wnt pathway, thereby further contributing to the role of Hippo signaling in preventing proliferation and stem cell expansion (Konsavage and Yochum, 2012). The relevance of the Wnt antagonizing effects of YAP in controlling intestinal stem cell expansion after regeneration was recently uncovered in an elegant series of experiments performed in the Camargo laboratory (Barry et al., 2012). Barry et al. (2012) report that epithelialspecific overexpression of the YAP (S127A) mutant, which importantly is predominantly localized in the cytoplasm in this tissue, induces intestinal hypotrophy
Cell Stem Cell 12, January 3, 2013 ª2013 Elsevier Inc. 3
Cell Stem Cell
Previews
and loss of crypt base (Schlegelmilch et al., 2011). columnar stem cells. MechaThere are several possibilities nistically, YAP(S127A) exfor this contrasting phenotype pression results in abrogation including context-dependent of Wnt signaling in the intespathway interactions, differtine in vivo. In agreement ential roles of the Wnt pathwith previous reports, YAP way in either tissue, or subcelloss in the intestine only lular localization differences marginally affects intestinal of the YAP(S127A) mutant. homeostasis (Cai et al., While the biological differ2010); however, the effects ences underlying the discrepof YAP loss become signifiancy between the effects of cant when a Wnt-dependent YAP expression in the skin regenerative response is and the intestine are not yet induced either by g-irradiaentirely clear, in the gut itself tion or by adenovirus-medithe effects of YAP overexated R-spondin1 expression. pression are not unambigIn those cases, YAP loss uous either. In the current results in a rapid expansion study by Barry et al. (2012), of the intestinal stem cell epithelial cell-specific YAP compartment and forma(S127A) expression results in a degenerative phenotype; tion of ectopic crypt regions however, when the same YAP and even microadenomas, which is in fact a phenotype mutant is expressed using very reminiscent of intestinal a ubiquitous promoter, intesFigure 1. A Novel Crosstalk Mechanism between the Hippo and Wnt APC loss as observed in tinal dysplasia with expansion Pathways Active Hippo signaling results in phosphorylation of YAP by LATS1/2 kinases. the APCmin mouse model. of undifferentiated progenitor Phosphorylated YAP remains located in the cytoplasm. Cytosolic-located YAP These data indicate that cells is observed (Camargo interacts directly with Dishevelled (DVL) and inhibits its nuclear translocation. YAP is involved in controlling et al., 2007). These results Nuclear DVL activates, parallel to the canonical Wnt pathway, a Wnt expresthe activity of the Wnt pathare especially intriguing as it sion program. YAP is crucial to restrain a Wnt-related regenerative response. Note that nuclear YAP (orange) functions as an oncogene and induces tranway during regeneration and indicates that the Hippo pathscription of a proliferation-inducing and antiapoptotic gene expression thereby also preventing tisway mediates potent paraprogram. Cytosolic YAP (green) functions as a tumor suppressor by inhibiting sue hypertrophy and dyscrine effects of the intestinal the Wnt pathway. plasia. The precise mechastroma, a concept that is in nism by which this occurs is line with a recent study reportnot entirely resolved yet, although it is tutive activation of the Wnt pathway seen ing that YAP expression indeed has parasuggested by Barry et al. (2012) that it in the vast majority of colorectal cancers crine functions and promotes secretion of does not involve sequestering of b-cate- (CRCs). Consequently, the Wnt target the EGFR ligand amphiregulin (Zhang nin in the cytoplasm or inhibition of gene YAP is upregulated in many CRCs. et al., 2009). GSK3b function within the b-catenin Interestingly, Barry et al. (2012) now idenTo conclude, the current work suggests degradation complex, which are two pre- tify a small fraction of CRCs that show low that YAP is a tumor suppressor gene in viously reported mechanisms by which expression of YAP protein and that have CRC, as Barry et al. (2012) additionally cytosolic YAP negatively regulates a dismal prognosis. The mechanism by showed that patients with low YAP Wnt signaling (Konsavage and Yochum, which YAP expression is restricted in expression levels have a poor prognosis 2012). Instead, Barry et al. (2012) propose these patients is unclear, but it could and overexpression of YAP results in a novel mechanism in which cytoplasmic involve promoter methylation that is impaired subcutaneous tumor growth of YAP directly inhibits nuclear translocation also described to be responsible for de- the DLD-1 CRC cell line. Intriguingly, of Dishevelled proteins where it promotes creased expression of other negative these findings appear to be counterintuiWnt target gene expression, in a parallel regulators of the Wnt pathway. tive based on previous work. Two recent It should be noted that several of reports showed that shRNA-mediated manner to the canonical b-catenin mediated activity of this pathway (Figure 1). the findings by Barry et al. (2012) con- downregulation of YAP in a panel of In many respects, cancer can be trast with previous paradigms of YAP CRC cell lines inhibits colony formation perceived as a disease in which stem function that were established in the field. and subcutaneous tumor growth (Koncell proliferation is no longer restricted First of all, the effects of epithelial cell- savage et al., 2012; Zhou et al., 2011), and causes tissue overpopulation. This specific YAP overexpression in the intes- which would be inconsistent with a tumor is often a consequence of mutations tine are opposite to the effects of YAP suppressor role for YAP in the intestine. causing activation of pathways promoting overexpression in the skin where it One possibility for resolving these opposstem cell proliferation and self-renewal. A strongly promotes stem cell expansion ing findings can be reached by appreprime example of this notion is the consti- and results in thickening of the skin ciating the different functions YAP has 4 Cell Stem Cell 12, January 3, 2013 ª2013 Elsevier Inc.
Cell Stem Cell
Previews depending on its subcellular localization. In this respect, nuclear YAP is thought to function mainly as an oncogene and promotes proliferation and expression of antiapoptotic proteins, while cytoplasmic YAP is a typical tumor suppressor that downregulates the Wnt pathway. If this hypothesis is true, it will be a true challenge to appropriately target this molecule for clinical benefit. Clever strategies need to be developed that selectively inhibit the oncogenic properties of this protein while promoting the tumor suppressor functions. Potentially, this could be achieved by interfering with the YAP-TEAD interaction or by inhibiting its nuclear translocation. In any case, it will be interesting to follow how efforts to manipulate YAP function will develop.
REFERENCES Barry, E.R., Morikawa, T., Butler, B.L., Shrestha, K., de la Rosa, R., Yan, K.S., Fuchs, C.S., Magness, S.T., Smits, R., Ogino, S., et al. (2012). Nature. Published online November 25, 2012. http://dx.doi.org/10.1038/nature11693. Cai, J., Zhang, N., Zheng, Y., de Wilde, R.F., Maitra, A., and Pan, D. (2010). Genes Dev. 24, 2383–2388. Camargo, F.D., Gokhale, S., Johnnidis, J.B., Fu, D., Bell, G.W., Jaenisch, R., and Brummelkamp, T.R. (2007). Curr. Biol. 17, 2054–2060. Kim, K.A., Kakitani, M., Zhao, J., Oshima, T., Tang, T., Binnerts, M., Liu, Y., Boyle, B., Park, E., Emtage, P., et al. (2005). Science 309, 1256–1259. Konsavage, W.M., Jr., and Yochum, G.S. (2012). Acta Biochim Biophys Sin (Shanghai). Published online September 30, 2012. http://dx.doi.org/10. 1093/abbs/gms084.
Konsavage, W.M., Jr., Kyler, S.L., Rennoll, S.A., Jin, G., and Yochum, G.S. (2012). J. Biol. Chem. 287, 11730–11739. Mauviel, A., Nallet-Staub, F., and Varelas, X. (2012). Oncogene 31, 1743–1756. Schlegelmilch, K., Mohseni, M., Kirak, O., Pruszak, J., Rodriguez, J.R., Zhou, D., Kreger, B.T., Vasioukhin, V., Avruch, J., Brummelkamp, T.R., and Camargo, F.D. (2011). Cell 144, 782–795. Zhang, J., Ji, J.Y., Yu, M., Overholtzer, M., Smolen, G.A., Wang, R., Brugge, J.S., Dyson, N.J., and Haber, D.A. (2009). Nat. Cell Biol. 11, 1444–1450. Zhou, D., Zhang, Y., Wu, H., Barry, E., Yin, Y., Lawrence, E., Dawson, D., Willis, J.E., Markowitz, S.D., Camargo, F.D., and Avruch, J. (2011). Proc. Natl. Acad. Sci. USA 108, E1312– E1320.
Cell Stem Cell 12, January 3, 2013 ª2013 Elsevier Inc. 5