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The ErbB-4 receptor protein-tyrosine kinase is proteolytically processed by membrane proteases in response to the ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation resulting in the cytoplasmic fragment translocating to the cell nucleus. The WW domain-containing co-transcriptional activator Yes-associated protein (YAP) associates physically with the full-length ErbB-4 receptor and functionally with the ErbB-4 cytoplasmic fragment in the nucleus. The YAP·ErbB4 complex is mediated by the first WW domain of YAP and the most carboxyl-terminal PPXY motif of ErbB-4. In human tissues, we documented the expression of YAP1 with a single WW domain and YAP2 with two WW domains. It is known that the COOH-terminal fragment of ErbB4 does not have transcriptional activity by itself; however, we show here that in the presence of YAP its transcriptional activity is revealed. There is a difference in the extent of transactivation activity among YAP isoforms: YAP2 is the stronger activator compared with YAP1. This transactivation is abolished by mutations that abrogate the YAP·ErbB4 complex formation. The unphosphorylatable mutation that increases the nuclear localization of YAP increases transcription activity. The COOH-terminal fragment of ErbB-4 and full-length YAP2 overexpressed in cells partially co-localize to the nucleus. Our data indicate that YAP is a potential signaling partner of the full-length ErbB4 receptor at the membrane and of the COOH-terminal fragment of ErbB-4 that translocates to the nucleus to regulate transcription. The ErbB-4 receptor protein-tyrosine kinase is proteolytically processed by membrane proteases in response to the ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation resulting in the cytoplasmic fragment translocating to the cell nucleus. The WW domain-containing co-transcriptional activator Yes-associated protein (YAP) associates physically with the full-length ErbB-4 receptor and functionally with the ErbB-4 cytoplasmic fragment in the nucleus. The YAP·ErbB4 complex is mediated by the first WW domain of YAP and the most carboxyl-terminal PPXY motif of ErbB-4. In human tissues, we documented the expression of YAP1 with a single WW domain and YAP2 with two WW domains. It is known that the COOH-terminal fragment of ErbB4 does not have transcriptional activity by itself; however, we show here that in the presence of YAP its transcriptional activity is revealed. There is a difference in the extent of transactivation activity among YAP isoforms: YAP2 is the stronger activator compared with YAP1. This transactivation is abolished by mutations that abrogate the YAP·ErbB4 complex formation. The unphosphorylatable mutation that increases the nuclear localization of YAP increases transcription activity. The COOH-terminal fragment of ErbB-4 and full-length YAP2 overexpressed in cells partially co-localize to the nucleus. Our data indicate that YAP is a potential signaling partner of the full-length ErbB4 receptor at the membrane and of the COOH-terminal fragment of ErbB-4 that translocates to the nucleus to regulate transcription. Cells are continuously exposed to diverse stimuli ranging from soluble paracrine and endocrine factors to signaling molecules on neighboring cells. These extracellular signals are transduced to cell nuclei to achieve an appropriate developmental or proliferative response. Receptor protein-tyrosine kinases play pivotal roles in this process. Upon binding of their cognate ligands, the intrinsic protein-tyrosine kinase activity of the receptor is significantly elevated and initiates a network of signaling pathways including the well characterized Ras/mitogen-activated protein kinase and the signal transducers and activators of transcription pathways (1Hunter T. Cell. 2000; 100: 113-127Abstract Full Text Full Text PDF PubMed Scopus (2278) Google Scholar, 2Schlessinger J. Cell. 2000; 103: 193-200Abstract Full Text Full Text PDF PubMed Scopus (3555) Google Scholar, 3Carpenter G. Exp. Cell Res. 2003; 284: 66-77Crossref PubMed Scopus (206) Google Scholar). Whereas many cell surface receptors transmit signals to the nucleus through complex protein cascades, several examples of membrane receptors translocating itself to the nucleus have been described (4Carpenter G. Curr. Opin. Cell Biol. 2003; 15: 143-148Crossref PubMed Scopus (144) Google Scholar, 5Wells A. Marti U. Nat. Rev. 2002; 3: 1-6Crossref Scopus (120) Google Scholar). In the case of ErbB-1, the epidermal growth factor receptor, addition of its cognate ligand causes translocation of the ligand-receptor complex to the nucleus and the complex binds to the cyclin D1 promoter activating its transcription (6Lin S.Y. Makino K. Xia W. Matin A. Wen Y. Kwong K.Y. Bourguignon L. Hung M.C. Nat. Cell Biol. 2001; 3: 802-808Crossref PubMed Scopus (903) Google Scholar). ErbB-3 (7Offterdinger M. Schofer C. Weipoltshammer K. Grunt T.W. J. Cell Biol. 2002; 157: 929-940Crossref PubMed Scopus (177) Google Scholar) and fibroblast growth factor receptor I (8Reilly J.F. Maher P.A. J. Cell Biol. 2001; 152: 1307-1312Crossref PubMed Scopus (202) Google Scholar, 9Maher P.A. J. Cell Biol. 1996; 134: 529-536Crossref PubMed Scopus (200) Google Scholar) have been also reported to be present in nucleus. Recently, it has been suggested that ErbB-4, the newest member of the epidermal growth factor protein-tyrosine kinase receptor family, activates gene expression in a more direct manner (10Ni C.Y. Murphy M.P. Golde T.E. Carpenter G. Science. 2001; 294: 2179-2181Crossref PubMed Scopus (759) Google Scholar, 11Lee H.J. Jung K.M. Huang Y.Z. Bennett L.B. Lee J.S. Mei L. Kim T.W. J. Biol. Chem. 2002; 277: 6318-6323Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar). The binding of its ligand, heregulin, or activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate provokes an ectodomain cleavage by a metalloprotease tumor necrosis factor-α-converting enzyme, followed by a subsequent cleavage by γ-secretase that release the ErbB-4 intracellular domain fragment from the membrane. The processing by γ-secretase facilitates the translocation of the COOH-terminal fragment of ErbB-4 (CTF) 1The abbreviations used are: CTF, COOH-terminal fragment of ErbB-4; HA, hemagglutinin; GFP, green fluorescent protein; PDZ, PSD-95/discs large/ZO-1; APP, amyloid precursor protein; WT, wild-type; PI3K, phosphatidylinositol 3-kinase; YAP, Yes-associated protein. to the nucleus where it may affect the transcription of target genes. Similar mechanisms have been described for the proteolytic processing of the Notch receptor and the Alzheimer's amyloid precursor protein (APP) (12Artavanis-Tsakonas S. Rand M.D. Lake R.J. Science. 1999; 284: 770-776Crossref PubMed Scopus (4950) Google Scholar, 13Fortini M.E. Nat. Rev. 2002; 3: 673-684Crossref Scopus (345) Google Scholar, 14Cao X. Sudhof T.C. Science. 2001; 293: 115-120Crossref PubMed Scopus (1058) Google Scholar). This process is called regulated intramembrane proteolysis and it represents a relatively new paradigm of signal transduction (15Heldin C.H. Ericsson J. Science. 2001; 294: 2111-2113Crossref PubMed Scopus (33) Google Scholar, 16Ebinu J.O. Yankner B.A. Neuron. 2002; 34: 499-502Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). In Notch-1 signaling, the ligand binding causes intra-membrane cleavage of Notch-1 and generation of a transcriptionally active fragment. The Notch signaling pathway plays an important role in the cell-fate specification process in multicellular organisms. The intracellular fragment of Notch is translocated to nucleus and binds directly to downstream transcription factors of the C promoter binding factor/suppressor of hairless/Lag-1 family, to control transcriptional repression and activation of Notch target genes (12Artavanis-Tsakonas S. Rand M.D. Lake R.J. Science. 1999; 284: 770-776Crossref PubMed Scopus (4950) Google Scholar). In the case of APP, its intracellular fragment is produced by γ-secretase and translocates to the nucleus to form a multimeric complex with the nuclear adaptor protein Fe65 and the histone acetyltransferase Tip60. This multicomponent complex is able to activate transcription via Gal4 or LexA reporters (14Cao X. Sudhof T.C. Science. 2001; 293: 115-120Crossref PubMed Scopus (1058) Google Scholar). In that experimental system, a robust transcriptional activation was observed only when the COOH-terminal fragment of APP was co-expressed with Fe65; the COOH-terminal fragment alone was not active. Fe65 is a typical adaptor protein composed of a WW domain and two PTB domains. The PTB1 domain binds to the histone acetyltransferase Tip60 and the PTB2 domain interacts with the cytoplasmic tail of APP (14Cao X. Sudhof T.C. Science. 2001; 293: 115-120Crossref PubMed Scopus (1058) Google Scholar, 17Fiore F. Zambrano N. Minopoli G. Donini V. Duilio A. Russo T. J. Biol. Chem. 1995; 270: 30853-30856Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar). Isoforms of the ErbB-4 receptor generated by alternative splicing have been described (Ref. 3Carpenter G. Exp. Cell Res. 2003; 284: 66-77Crossref PubMed Scopus (206) Google Scholar and Fig. 1a) including the JM-a isoform that is sensitive to the cleavage, whereas the JM-b isoform is insensitive to the cleavage because of the sequence difference in the juxtamembrane region (18Elenius K. Corfas G. Paul S. Choi C.J. Rio C. Plowman G.D. Klagsbrun M. J. Biol. Chem. 1997; 272: 26761-26768Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). The other isoform contains a sequence change in the phosphatidylinositol 3-kinase (PI3K) binding region within the cytoplasmic domain (19Elenius K. Choi C.J. Paul S. Santiestevan E. Nishi E. Klagsbrun M. Oncogene. 1999; 18: 2607-2615Crossref PubMed Scopus (145) Google Scholar, 20Kainulainen V. Sundvall M. Maatta J.A. Santiestevan E. Klagsbrun M. Elenius K. J. Biol. Chem. 2000; 275: 8641-8649Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). This is in an isoform and the other isoform that contains is The that was to to the nucleus contains a protein-tyrosine kinase and the domain Y.Z. S. M. Mei L. Neuron. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, C.Y. Carpenter G. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the ErbB-4 sequence we several that potential binding for WW domains. The WW domain is a composed of M. U. S. A. 1995; PubMed Scopus Google Scholar, M. Full Text PDF PubMed Scopus Google Scholar). The domain binds M. T. Cell. 2000; 103: Full Text Full Text PDF PubMed Scopus Google Scholar). The of WW binds PPXY The PPXY in the COOH-terminal region of ErbB-4 the motif that is by the I WW domains. we that the WW domain-containing Yes-associated protein (YAP) and its with the cytoplasmic region of ErbB-4 and the COOH-terminal fragment of transcription in the Gal4 YAP has been characterized a for several transcription factors including the K. Y. Y. J. 1999; 18: PubMed Scopus Google the of transcription factors A. Y. 2001; 15: PubMed Scopus Google and S. E. M. L. Y. A. M. M. G. G. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). it has been reported that the localization of YAP in the nucleus is regulated by kinase and subsequent binding to protein S. M. J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, F. P.A. M. A. T. Y. J. 2000; PubMed Scopus Google Scholar). of the or membrane signals that with YAP have been This is the first the stimulation of transcription by ErbB-4 in complex with that region of human YAP1 and YAP2 from and M. A. K. T. M. K. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google and The fragment was from the and the the to expression and The expression full-length ErbB-4 with COOH-terminal H.J. Jung K.M. Huang Y.Z. Bennett L.B. Lee J.S. Mei L. Kim T.W. J. Biol. Chem. 2002; 277: 6318-6323Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, Y.Z. S. M. Mei L. Neuron. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and have been described H.J. Jung K.M. Huang Y.Z. Bennett L.B. Lee J.S. Mei L. Kim T.W. J. Biol. 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Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google is here YAP1 and the new YAP with two WW is The difference in the sequence YAP1 and YAP2 is an of the WW domain its and the of the sequence in YAP2 that YAP2 is a splicing The WW domain of human YAP2 from the WW domain of YAP by in the in the of the The sequence of human YAP2 sequence with the YAP, that YAP2 is most the human of YAP1 and YAP2 with ErbB-4 through the WW human and ErbB-4, the isoform of the full-length ErbB-4 and YAP1 or YAP2 in and the cell was with The was with to the of ErbB-4. In the presence of YAP1 or ErbB-4 was and that YAP1 or YAP2 associates with ErbB-4 in cells. YAP2 more in of ErbB-4 YAP1 and that YAP2 associates with ErbB-4 stronger YAP1 to this is mediated by the WW domain of a WW domain was in the and the to on A. E. S. M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, Zambrano N. Minopoli G. F. Russo T. M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar) and on the of the WW domain M. E. J. M. M. 1996; PubMed Scopus Google Scholar) the domain in of ligand The WW domain mutation in YAP1 abolished the binding to ErbB-4 the mutation of the WW domain in YAP2 not have on binding to ErbB-4 These indicate that the first WW domain of is for the with ErbB-4 not the WW domain in of the in YAP the to ErbB-4 has been reported that the in YAP is by a protein and it is by the protein S. M. J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The binding by causes translocation of YAP from the from the nucleus. the of this for the binding to ErbB-4, the at was to and binding was by The mutation of at in YAP1 and YAP2 the binding to ErbB-4 and with ErbB-4 through the PPXY in the that to PPXY in the in the PPXY to There are two PPXY in the region of ErbB-4 at and the first PPXY was and the was The that the of in the most COOH-terminal PPXY region abolished the binding to YAP and the the binding to was not by the mutation of the first PPXY sequence and the that the and ErbB-4 is through the WW domain first WW domain in in YAP and the most COOH-terminal PPXY sequence in ErbB-4. These data are in with the of the binding of for YAP1 WW domain from and membrane S. M. Biol. Chem. 1997; PubMed Scopus Google Scholar). The YAP for of via the Gal4 that the is in the the was in cells and with ErbB-4 of the nuclear localization and localization in cells The localization is compared with the this of nuclear in cells This data a from the Carpenter with the and cell (10Ni C.Y. Murphy M.P. Golde T.E. Carpenter G. Science. 2001; 294: 2179-2181Crossref PubMed Scopus (759) Google Scholar). It was also that the with the kinase domain has an to transcription in the Gal4 in to the we have used the Gal4 transactivation (10Ni C.Y. Murphy M.P. Golde T.E. Carpenter G. Science. 2001; 294: 2179-2181Crossref PubMed Scopus (759) Google however, in the presence of YAP1 or The Gal4 binding domain with the COOH-terminal fragment or with the of the kinase domain of ErbB-4 was with the in cells and the activity was only the COOH-terminal fragment with the kinase domain transcription the Gal4 control the fragment or the control in the we of YAP1 or YAP2 significantly the and of and and the Gal4 These indicate that transcription and that YAP2 is a stronger of transcription YAP1. The of YAP with the ErbB-4 for the subsequent we used the of in the Gal4 because the fragment has not been that the transactivation by YAP is because of the direct with the we used YAP2 with a mutation in the WW domain that does not with ErbB-4 in the Gal4 YAP2 with the mutation in the WW domain the YAP2 with the mutation in the first WW domain not activate transcription at mutation of the PPXY sequence of the that is for binding to YAP also abolished the stimulation of transcription on the COOH-terminal fragment or the kinase domain the not have in the and These data indicate that the transactivation is by the complex mediated by the WW domain of YAP and the most COOH-terminal PPXY sequence of the It has been reported that YAP is in the and its nuclear localization is by the binding of S. M. J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). It has also been known that the mutation of to increases transactivation activity of YAP because of a nuclear localization of YAP and to the in the Gal4 in the the full-length ErbB-4, the mutation the binding of YAP, this mutation a transactivation compared with the in with the reported data in the the mediated transcription S. M. J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of YAP described here may be because of the change in localization of YAP to the nucleus and its to the membrane full-length The with YAP in the produced by the γ-secretase cleavage with YAP in cells with and The localization in the nucleus and cytoplasmic In a of the with the in the cell nuclei that YAP in the nucleus with the from γ-secretase of YAP in the human YAP1 and YAP2 described here for the first and the in their transcriptional activity was we to the expression of YAP in of the in human tissues, used we the that YAP1 and YAP2 be and The sequence of the YAP2 and the of human YAP1 and YAP2 in the we from two the of for the YAP1 was not the with was in most with the to be the YAP2 the by direct sequence and the known YAP YAP2 The to a new isoform with an of we this isoform This sequence has been to the data with the of and the human to this has been also to the data with the The observed in many including and the expression of the was to the in the and In the only the was that the YAP2 isoform be at in the compared with the other The YAP from and not YAP expression has been documented in by M. Oncogene. Google Scholar). that the transcriptional YAP associates with the cytoplasmic region of ErbB-4 and transcription of the CTF, the proteolytic fragment of the of also the YAP and the full-length ErbB-4 in the and YAP and the of ErbB-4 in the nucleus the Gal4 These indicate that YAP may with the ErbB-4 receptor at the membrane and also with the in the nucleus. on the data we that the of ErbB4 produced by γ-secretase cleavage, translocates with YAP to the nucleus ligand or YAP may not only a transcriptional for the CTF, also may a protein for the translocation of the from the membrane to the nucleus. The of the the localization of YAP and the with other signaling the role of of YAP and of ErbB4 in and the of transcriptional activation of the and its nuclear It has been reported that YAP to the membrane in cells with the domain through its COOH-terminal domain binding sequence M. J. Cell Biol. 1999; PubMed Scopus Google Scholar). 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Oncogene. 1999; 18: 2607-2615Crossref PubMed Scopus (145) Google Scholar). also have a new of YAP2 with of This is in not in The sequence of the does not have sequence to known or domains. we not the YAP1 in the we not YAP1 in the and in the human data human YAP1 many of YAP2 and are present in the data the data that YAP1 is not in and the of YAP1 in the human and data that YAP2 is the isoform and YAP1 is a isoform in human it is that YAP1 is only or of In the of a that has M.E. M. U. S. A. PubMed Scopus Google in addition to the of YAP2 and YAP2 with the we a in the WW domain is in and M. This isoform may a form of YAP in In we have most splicing that and YAP2 in human and two YAP2 and YAP2 in documented that YAP2 is a stronger transcriptional The difference YAP1 and YAP2 in the is the of WW and the of in the transcription activation region in YAP1. The presence of the WW domain have a and the have an on transcription. In the mutation of the WW domain the transcription activity by an In this the of the protein that associates with the WW domain of YAP2 be The signaling among YAP splicing The transcriptional activation of the COOH-terminal fragment of ErbB-4 described here for this new signaling for the role of complex in the nucleus are The to the nucleus with YAP and with several transcription factors on the promoter to activate transcription In this the a of YAP for the transcription This is to the COOH-terminal fragment of APP and a WW domain protein complex described by and Sudhof (14Cao X. Sudhof T.C. Science. 2001; 293: 115-120Crossref PubMed Scopus (1058) Google Scholar). The COOH-terminal fragment of APP produced by γ-secretase itself does not have transcriptional activity and a the transcription factor that the complex to the promoter has not been in of the transcription factors binding for ErbB-4 or in the nucleus is of that the alone to the nucleus where YAP in complex with transcription S. E. M. L. Y. A. M. M. G. G. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google K. Y. Y. J. 1999; 18: PubMed Scopus Google or A. Y. 2001; 15: PubMed Scopus Google Scholar) In the case of and the complex be of an because the may with transcription factors for binding to the WW domain of In in the case of the translocation of the to the nucleus in a protein complex composed of because the binding is not through the WW and its translocation affect the activity of the transcription by transcription factors directly may downstream of YAP·ErbB4 Kim from for the ErbB-4 from the for the for and and Paul and for
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