Regulation of p73 by Hck through kinase-dependent and independent mechanisms
Tóm tắt
p73, a p53 family member is a transcription factor that plays a role in cell cycle, differentiation and apoptosis. p73 is regulated through post translational modifications and protein interactions. c-Abl is the only known tyrosine kinase that phosphorylates and activates p73. Here we have analyzed the role of Src family kinases, which are involved in diverse signaling pathways, in regulating p73. Exogenously expressed as well as cellular Hck and p73 interact in vivo. In vitro binding assays show that SH3 domain of Hck interacts with p73. Co-expression of p73 with Hck or c-Src in mammalian cells resulted in tyrosine phosphorylation of p73. Using site directed mutational analysis, we determined that Tyr-28 was the major site of phosphorylation by Hck and c-Src, unlike c-Abl which phosphorylates Tyr-99. In a kinase dependent manner, Hck co-expression resulted in stabilization of p73 protein in the cytoplasm. Activation of Hck in HL-60 cells resulted in tyrosine phosphorylation of endogenous p73. Both exogenous and endogenous Hck localize to the nuclear as well as cytoplasmic compartment, just as does p73. Ectopically expressed Hck repressed the transcriptional activity of p73 as determined by promoter assays and semi-quantitative RT-PCR analysis of the p73 target, Ipaf and MDM2. SH3 domain- dependent function of Hck was required for its effect on p73 activity, which was also reflected in its ability to inhibit p73-mediated apoptosis. We also show that Hck interacts with Yes associated protein (YAP), a transcriptional co-activator of p73, and shRNA mediated knockdown of YAP protein reduces p73 induced Ipaf promoter activation. We have identified p73 as a novel substrate and interacting partner of Hck and show that it regulates p73 through mechanisms that are dependent on either catalytic activity or protein interaction domains. Hck-SH3 domain-mediated interactions play an important role in the inhibition of p73-dependent transcriptional activation of a target gene, Ipaf, as well as apoptosis.
Tài liệu tham khảo
Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X: et al, Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell. 1997, 90: 809-819. 10.1016/S0092-8674(00)80540-1
Ozaki T, Nakagawara A: p73, a sophisticated p53 family member in the cancer world. Cancer Sci. 2005, 96: 729-737. 10.1111/j.1349-7006.2005.00116.x
Melino G, De LV, Vousden KH: p73: Friend or foe in tumorigenesis. Nat Rev Cancer. 2002, 2: 605-615. 10.1038/nrc861
Harms K, Nozell S, Chen X: The common and distinct target genes of the p53 family transcription factors. Cell Mol Life Sci. 2004, 61: 822-842. 10.1007/s00018-003-3304-4
Jost CA, Marin MC, Kaelin WG: p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature. 1997, 389: 191-194. 10.1038/38298
De LV, Melino G: Evolution of functions within the p53/p63/p73 family. Ann N Y Acad Sci. 2000, 926: 90-100.
Zhu J, Jiang J, Zhou W, Chen X: The potential tumor suppressor p73 differentially regulates cellular p53 target genes. Cancer Res. 1998, 58: 5061-5065.
Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A: et al, p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature. 2000, 404: 99-103. 10.1038/35003607
Jain N, Gupta S, Sudhakar C, Radha V, Swarup G: Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin. J Biol Chem. 2005, 280: 36664-36673. 10.1074/jbc.M413261200
Irwin MS, Kaelin WG: p53 family update: p73 and p63 develop their own identities. Cell Growth Differ. 2001, 12: 337-349.
Dobbelstein M, Strano S, Roth J, Blandino G: p73-induced apoptosis: a question of compartments and cooperation. Biochem Biophys Res Commun. 2005, 331: 688-693. 10.1016/j.bbrc.2005.03.155
Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG, Levrero M, Wang JY: The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature. 1999, 399: 806-809. 10.1038/21690
Miyazaki K, Ozaki T, Kato C, Hanamoto T, Fujita T, Irino S, Watanabe K, Nakagawa T, Nakagawara A: A novel HECT-type E3 ubiquitin ligase, NEDL2, stabilizes p73 and enhances its transcriptional activity. Biochem Biophys Res Commun. 2003, 308: 106-113. 10.1016/S0006-291X(03)01347-0
Kramer S, Ozaki T, Miyazaki K, Kato C, Hanamoto T, Nakagawara A: Protein stability and function of p73 are modulated by a physical interaction with RanBPM in mammalian cultured cells. Oncogene. 2005, 24: 938-944. 10.1038/sj.onc.1208257
Stros M, Ozaki T, Bacikova A, Kageyama H, Nakagawara A: HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J Biol Chem. 2002, 277: 7157-7164. 10.1074/jbc.M110233200
Ozaki T, Watanabe K, Nakagawa T, Miyazaki K, Takahashi M, Nakagawara A: Function of p73, not of p53, is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB. Oncogene. 2003, 22: 3231-3242. 10.1038/sj.onc.1206382
Fulco M, Costanzo A, Merlo P, Mangiacasale R, Strano S, Blandino G, Balsano C, Lavia P, Levrero M: p73 is regulated by phosphorylation at the G2/M transition. J Biol Chem. 2003, 278: 49196-49202. 10.1074/jbc.M304921200
Gaiddon C, Lokshin M, Gross I, Levasseur D, Taya Y, Loeffler JP, Prives C: Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73. J Biol Chem. 2003, 278: 27421-27431. 10.1074/jbc.M300251200
Aqeilan RI, Pekarsky Y, Herrero JJ, Palamarchuk A, Letofsky J, Druck T, Trapasso F, Han SY, Melino G, Huebner K: et al, Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc Natl Acad Sci USA. 2004, 101: 4401-4406. 10.1073/pnas.0400805101
Hanamoto T, Ozaki T, Furuya K, Hosoda M, Hayashi S, Nakanishi M, Yamamoto H, Kikuchi H, Todo S, Nakagawara A: Identification of protein kinase A catalytic subunit beta as a novel binding partner of p73 and regulation of p73 function. J Biol Chem. 2005, 280: 16665-16675. 10.1074/jbc.M414323200
Watanabe K, Ozaki T, Nakagawa T, Miyazaki K, Takahashi M, Hosoda M, Hayashi S, Todo S, Nakagawara A: Physical interaction of p73 with c-Myc and MM1, a c-Myc-binding protein, and modulation of the p73 function. J Biol Chem. 2002, 277: 15113-15123. 10.1074/jbc.M111281200
Agami R, Blandino G, Oren M, Shaul Y: Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature. 1999, 399: 809-813. 10.1038/21697
Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY, Lu H, Kharbanda S, Weichselbaum R, Kufe D: p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature. 1999, 399: 814-817. 10.1038/21704
Sanchez-Prieto R, Sanchez-Arevalo VJ, Servitja JM, Gutkind JS: Regulation of p73 by c-Abl through the p38 MAP kinase pathway. Oncogene. 2002, 21: 974-979. 10.1038/sj.onc.1205134
Thomas SM, Brugge JS: Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997, 13: 513-609. 10.1146/annurev.cellbio.13.1.513
Briggs SD, Sharkey M, Stevenson M, Smithgall TE: SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by theNef protein of HIV-1. J Biol Chem. 1997, 272: 17899-17902. 10.1074/jbc.272.29.17899
Liu X, Pawson T: Biochemistry of the Src protein-tyrosine kinase: regulation by SH2 and SH3 domains. Recent Prog Horm Res. 1994, 49: 149-60.
Ernst M, Gearing DP, Dunn AR: Functional and biochemical association of Hck with the LIF/IL-6 receptor signal transducing subunit gp130 in embryonic stem cells. EMBO J. 1994, 13: 1574-1584.
Quintrell N, Lebo R, Varmus H, Bishop JM, Pettenati MJ, Le Beau MM, Diaz MO, Rowley JD: Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. Mol Cell Biol. 1987, 7: 2267-2275.
Ziegler SF, Marth JD, Lewis DB, Perlmutter RM: Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin. Mol Cell Biol. 1987, 7: 2276-2285.
Lock P, Ralph S, Stanley E, Boulet I, Ramsay R, Dunn AR: Two isoforms of murine hck, generated by utilization of alternative translational initiation codons, exhibit different patterns of subcellular localization. Mol Cell Biol. 1991, 11: 4363-4370.
Bosco MC, Curiel RE, Zea AH, Malabarba MG, Ortaldo JR, Espinoza-Delgado I: IL-2 signaling in human monocytes involves the phosphorylation and activation of p59hck. J Immunol. 2000, 164: 4575-4585.
Ward AC, Monkhouse JL, Csar XF, Touw IP, Bello PA: The Src-like tyrosine kinase Hck is activated by granulocyte colony-stimulating factor (G-CSF) and docks to the activated G-CSF receptor. Biochem Biophys Res Commun. 1998, 251: 117-123. 10.1006/bbrc.1998.9441
English BK, Ihle JN, Myracle A, Yi T: Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages. J Exp Med. 1993, 178: 1017-1022. 10.1084/jem.178.3.1017
Boulet I, Ralph S, Stanley E, Lock P, Dunn AR, Green SP, Phillips WA: Lipopolysaccharide- and interferon-gamma-induced expression of hck and lyn tyrosine kinases in murine bone marrow-derived macrophages. Oncogene. 1992, 7: 703-710.
Shivakrupa R, Radha V, Sudhakar C, Swarup G: Physical and functional interaction between Hck tyrosine kinase and guanine nucleotide exchange factor C3G results in apoptosis, which is independent of C3G catalytic domain. J Biol Chem. 2003, 278: 52188-52194. 10.1074/jbc.M310656200
Scholz G, Cartledge K, Dunn AR: Hck enhances the adherence of lipopolysaccharide-stimulated macrophages via Cbl and phosphatidylinositol 3-kinase. J Biol Chem. 2000, 275: 14615-14623. 10.1074/jbc.275.19.14615
Scott MP, Zappacosta F, Kim EY, Annan RS, Miller WT: Identification of novel SH3 domain ligands for the Src family kinase Hck. Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1. J Biol Chem. 2002, 277: 28238-28246. 10.1074/jbc.M202783200
Schreiner SJ, Schiavone AP, Smithgall TE: Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. J Biol Chem. 2002, 277: 45680-45687. 10.1074/jbc.M204255200
Yokoyama N, Miller WT: Biochemical properties of the Cdc42-associated tyrosine kinase ACK1. Substrate specificity, authphosphorylation, and interaction with Hck. J Biol Chem. 2003, 278: 47713-47723. 10.1074/jbc.M306716200
Tsai KK, Yuan ZM: c-Abl stabilizes p73 by a phosphorylation-augmented interaction. Cancer Res. 2003, 63: 3418-3424.
Tanis KQ, Veach D, Duewel HS, Bornmann WG, Koleske AJ: Two distinct phosphorylation pathways have additive effects on Abl family kinase activation. Mol Cell Biol. 2003, 23: 3884-3896. 10.1128/MCB.23.11.3884-3896.2003
Tschan MP, Grob TJ, Peters UR, Laurenzi VD, Huegli B, Kreuzer KA, Schmidt CA, Melino G, Fey MF, Tobler A: et al, Enhanced p73 expression during differentiation and complex p73 isoforms in myeloid leukemia. Biochem Biophys Res Commun. 2000, 277: 62-65. 10.1006/bbrc.2000.3627
Linnekin D, Howard OM, Park L, Farrar W, Ferris D, Longo DL: Hck expression correlates with granulocyte-macrophage colony-stimulating factor-induced proliferation in HL-60 cells. Blood. 1994, 84: 94-103.
Howlett CJ, Bisson SA, Resek ME, Tigley AW, Robbins SM: The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase. Biochem Biophys Res Commun. 1999, 257: 129-138. 10.1006/bbrc.1999.0427
Robbins SM, Quintrell NA, Bishop JM: Mercuric chloride activates the Src-family protein tyrosine kinase, Hck in myelomonocytic cells. Eur J Biochem. 2000, 267: 7201-7208. 10.1046/j.1432-1327.2000.01830.x
Mohn H, Le C V, Fischer S, Maridonneau-Parini I: The src-family protein-tyrosine kinase p59hck is located on the secretory granules in human neutrophils and translocates towards the phagosome during cell activation. Biochem J. 1995, 309: 657-665.
Robbins SM, Quintrell NA, Bishop JM: Myristoylation and differential palmitoylation of the HCK protein-tyrosine kinases govern their attachment to membranes and association with caveolae. Mol Cell Biol. 1995, 15: 3507-3515.
Astarie-Dequeker C, Carreno S, Cougoule C, Maridonneau-Parini I: The protein tyrosine kinase Hck is located on lysosomal vesicles that are physically and functionally distinct from CD63-positive lysosomes in human macrophages. J Cell Sci. 2002, 115: 81-89.
Radha V, Rajanna A, Swarup G: Phosphorylated guanine nucleotide exchange factor C3G, induced by pervanadate and Src family kinases localizes to the Golgi and subcortical actin cytoskeleton. BMC Cell Biol. 2004, 20 (5): 31-10.1186/1471-2121-5-31.
Zhao Y, Sudol M, Hanafusa H, Krueger J: Increased tyrosine kinase activity of c-Src during calcium-induced keratinocyte differentiation. Proc Natl Acad Sci USA. 1992, 89: 8298-8302. 10.1073/pnas.89.17.8298
David-Pfeuty T, Bagrodia S, Shalloway D: Differential localization patterns of myristoylated and nonmyristoylated c-Src proteins in interphase and mitotic c-Src overexpresser cells. J Cell Sci. 1993, 105: 613-628.
Radha V, Nambirajan S, Swarup G: Association of Lyn tyrosine kinase with the nuclear matrix and cell-cycle-dependent changes in matrix-associated tyrosine kinase activity. Eur J Biochem. 1996, 236: 352-359. 10.1111/j.1432-1033.1996.00352.x
Ren X, Cao C, Zhu L, Yoshida K, Kharbanda S, Weichselbaum R, Kufe D: Lyn tyrosine kinase inhibits nuclear export of the p53 tumor suppressor. Cancer Biol Ther. 2002, 1: 703-708.
He Z, Cho YY, Ma WY, Choi HS, Bode AM, Dong Z: Regulation of ultraviolet B-induced phosphorylation of histone H3 at serine 10 by Fyn kinase. J Biol Chem. 2005, 280: 2446-2454. 10.1074/jbc.M402053200
Sadasivam S, Gupta S, Radha V, Batta K, Kundu TK, Swarup G: Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis. Oncogene. 2005, 24 (4): 627-636. 10.1038/sj.onc.1208201
Fontemaggi G, Kela I, Amariglio N, Rechavi G, Krishnamurthy J, Strano S, Sacchi A, Givol D, Blandino G: Identification of direct p73 target genes combining DNA microarray and chromatin immunoprecipitation analyses. J Biol Chem. 2002, 277: 43359-43368. 10.1074/jbc.M205573200
Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G: Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem. 2001, 276: 15164-15173. 10.1074/jbc.M010484200
Strano S, Monti O, Pediconi N, Baccarini A, Fontemaggi G, Lapi E, Mantovani F, Damalas A, Citro G, Sacchi A: et al, The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage. Mol Cell. 2005, 18: 447-459. 10.1016/j.molcel.2005.04.008
Sudol M: Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene. 1994, 9: 2145-2152.
Nilsson J, Bjursell G, Kannius-Janson M: Nuclear Jak2 and transcription factor NF1-C2: a novel mechanism of prolactin signaling in mammary epithelial cells. Mol Cell Biol. 2006, 26: 5663-5674. 10.1128/MCB.02095-05
Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G: Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem. 2001, 276: 15164-15173. 10.1074/jbc.M010484200
Zeng X, Chen L, Jost CA, Maya R, Keller D, Wang X, Kaelin WG, Oren M, Chen J, Lu H: MDM2 suppresses p73 function without promoting p73 degradation. Mol Cell Biol. 1999, 19: 3257-3266.
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM: p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003, 11: 577-590. 10.1016/S1097-2765(03)00050-9
Chipuk JE, Green DR: Cytoplasmic p53: bax and forward. Cell Cycle. 2004, 3: 429-431.
Marchenko ND, Wolff S, Erster S, Becker K, Moll UM: Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J. 2007, 26: 923-934. 10.1038/sj.emboj.7601560
Yang C, Zhou W, Jeon MS, Demydenko D, Harada Y, Zhou H, Liu YC: Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol Cell. 2006, 21: 135-141. 10.1016/j.molcel.2005.11.014
Rossi M, De LV, Munarriz E, Green DR, Liu YC, Vousden KH, Cesareni G, Melino G: The ubiquitin-protein ligase Itch regulates p73 stability. EMBO J. 2005, 24: 836-848. 10.1038/sj.emboj.7600444
Radha V, Sudhakar C, Swarup G: Induction of p53 dependent apoptosis upon overexpression of a nuclear protein tyrosine phosphatase. FEBS Lett. 1999, 453: 308-312. 10.1016/S0014-5793(99)00734-6
Gupta S, Radha V, Furukawa Y, Swarup G: Direct transcriptional activation of human caspase-1 by tumor suppressor p53. J Biol Chem. 2001, 276: 10585-10588. 10.1074/jbc.C100025200
Yu JY, DeRuiter SL, Turner DL: RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc Natl Acad Sci USA. 2002, 99: 6047-6052. 10.1073/pnas.092143499