Yes-associated Protein and p53-binding Protein-2 Interact through Their WW and SH3 Domains

To understand the role of the Yes-associated protein (YAP), binding partners of its WW1 domain were isolated by a yeast two-hybrid screen. One of the interacting proteins was identified as p53-binding protein-2 (p53BP-2). YAP and p53BP-2 interacted in vitro and in vivo using their WW1 and SH3 domains, respectively. The YAP WW1 domain bound to the YPPPPY motif of p53BP-2, whereas the p53BP-2 SH3 domain interacted with the VPMRLR sequence of YAP, which is different from other known SH3 domain-binding motifs. By mutagenesis, we showed that this unusual SH3 domain interaction was due to the presence of three consecutive tryptophans located within the βC strand of the SH3 domain. A point mutation within this triplet, W976R, restored the binding selectivity to the general consensus sequence for SH3 domains, the PXXP motif. A constitutively active form of c-Yes was observed to decrease the binding affinity between YAP and p53BP-2 using chloramphenicol acetyltransferase/enzyme-linked immunosorbent assay, whereas the overexpression of c-Yes did not modify this interaction. Since overexpression of an activated form of c-Yes resulted in tyrosine phosphorylation of p53BP-2, we propose that the p53BP-2 phosphorylation, possibly in the WW1 domain-binding motif, might negatively regulate the YAP·p53BP-2 complex. To understand the role of the Yes-associated protein (YAP), binding partners of its WW1 domain were isolated by a yeast two-hybrid screen. One of the interacting proteins was identified as p53-binding protein-2 (p53BP-2). YAP and p53BP-2 interacted in vitro and in vivo using their WW1 and SH3 domains, respectively. The YAP WW1 domain bound to the YPPPPY motif of p53BP-2, whereas the p53BP-2 SH3 domain interacted with the VPMRLR sequence of YAP, which is different from other known SH3 domain-binding motifs. By mutagenesis, we showed that this unusual SH3 domain interaction was due to the presence of three consecutive tryptophans located within the βC strand of the SH3 domain. A point mutation within this triplet, W976R, restored the binding selectivity to the general consensus sequence for SH3 domains, the PXXP motif. A constitutively active form of c-Yes was observed to decrease the binding affinity between YAP and p53BP-2 using chloramphenicol acetyltransferase/enzyme-linked immunosorbent assay, whereas the overexpression of c-Yes did not modify this interaction. Since overexpression of an activated form of c-Yes resulted in tyrosine phosphorylation of p53BP-2, we propose that the p53BP-2 phosphorylation, possibly in the WW1 domain-binding motif, might negatively regulate the YAP·p53BP-2 complex. WW domains are small modules that mediate protein/protein interactions (1Bork P. Sudol M. Trends Biochem. Sci. 1994; 19: 531-533Abstract Full Text PDF PubMed Scopus (347) Google Scholar, 2Chen H.I. Sudol M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7819-7823Crossref PubMed Scopus (486) Google Scholar). The major features of the WW domain primary structure are (i) two conserved tryptophans spaced by 20–22 amino acids within the 40-amino acid long domain, (ii) a block of two or three aromatic amino acids located centrally between the two signature tryptophans, and (iii) a conserved proline located +3 to the second conserved tryptophan (3Sudol M. Prog. Biophys. Mol. Biol. 1996; 65: 113-132Crossref PubMed Scopus (251) Google Scholar). The three antiparallel β strands of WW domains form a hydrophobic patch that binds proline-rich or proline-containing motifs (4Macias M.J. Hyvonen M. Baraldi E. Schultz J. Sudol M. Saraste M. Oschkinat H. Nature. 1996; 382: 646-649Crossref PubMed Scopus (360) Google Scholar). Based on the ligand-binding specificity, one can divide WW domains into five groups. Group I WW domains bind to the core sequence PPXY (2Chen H.I. Sudol M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7819-7823Crossref PubMed Scopus (486) Google Scholar, 5Rentschler S. Linn H. Deininger K. Bedford M.T. Espanel X. Sudol M. Biol. Chem. 1999; 380: 431-442Crossref PubMed Scopus (98) Google Scholar). Group II WW domains interact with a long stretch of prolines interrupted by a leucine (6Ermekova K.S. Zambrano N. Linn H. Minopoli G. Gertler F. Russo T. Sudol M. J. Biol. Chem. 1997; 272: 32869-32877Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 7Bedford M.T. Chan D.C. Leder P. EMBO J. 1997; 16: 2376-2383Crossref PubMed Scopus (190) Google Scholar). Group III WW domains bind to PPR-containing motifs (8Bedford M.T. Sarbassova D. Xu J. Leder P. Yaffe M.B. J. Biol. Chem. 2000; 275: 10359-10369Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Group IV WW domains interact with phosphoserine that is followed by a proline (9Lu P.-J. Zhou X.Z. Shen M. Lu K.P. Science. 1999; 283: 1325-1328Crossref PubMed Scopus (588) Google Scholar). Group V WW domains interact with polyprolines interrupted by a glycine and flanked by arginine (10Komuro A. Saeki M. Kato S. J. Biol. Chem. 1999; 274: 36513-36519Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). A WW-like fold was identified in the platelet-derived growth factor receptor subfamily of tyrosine kinases (11Irusta P.M. DiMaio D. EMBO J. 1998; 17: 6912-6923Crossref PubMed Scopus (57) Google Scholar). SH3 domains are composed of 50–70 amino acids forming a structure containing multiple β sheets (12Xu W. Harrison S.C. Eck M.J. Nature. 1997; 385: 595-602Crossref PubMed Scopus (1244) Google Scholar). These modules also mediate protein/protein interactions through proline-rich motifs. Based on the binding specificity, the SH3 domains are divided into three major groups. Group I SH3 domains interact with basic-X-hydrophobic-proline-X-hydrophobic-proline (+XψPXψP), whereas Group II binds to hydrophobic-proline-X-hydrophobic-proline-X-basic (ψPXψPX+). Group III SH3 domains represented by the Eps8 family members select ligands with PXXDY consensus cores (13Mongiovi A.M. Romano P.R. Panni S. Mendoza M. Wong W.T. Musacchio A. Cesarini G. Di Fiore P.P. EMBO J. 1999; 18: 5300-5309Crossref PubMed Scopus (155) Google Scholar). Yes-associated protein (YAP),1 the first protein in which a WW domain was identified, is a phosphoprotein of 65 kDa that interacts with the SH3 domain of the c-yes proto-oncogene product, a non-receptor tyrosine kinase of the Src family. YAP expression is ubiquitous, with a high expression in ovaries (14Sudol M. Chen H.I. Bougeret C. Einbond A. Bork P. FEBS Lett. 1995; 369: 67-71Crossref PubMed Scopus (295) Google Scholar). YAP has two isoforms: a short form (YAP) that possesses only one WW domain (WW1) and a long form (LYAP) that has two WW domains (WW1 and WW2) (Fig. 1 A). In addition, there is a PDZ domain-binding motif, TWL, at the carboxyl-terminal end of YAP that allows the interaction with a submembranous scaffolding protein, EBP50 (ERM-binding phosphoprotein) (15Mohler P.J. Kreda S.M. Boucher R.C. Sudol M. Stutts M.J. Milgram S.L. J. Cell Biol. 1999; 147: 879-890Crossref PubMed Scopus (166) Google Scholar). Since the modular structure of YAP is reminiscent of adaptor-type signaling proteins, we have decided to partners of YAP to understand its the YAP WW1 domain to a expression we have identified two WW domain-binding protein and (2Chen H.I. Sudol M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7819-7823Crossref PubMed Scopus (486) Google Scholar). The of two ligands showed that the YAP WW1 domain binds to the PPXY core sequence has that YAP can also interact with binding a factor Chen K. EMBO J. 1999; 18: PubMed Scopus Google Scholar). In this using yeast two-hybrid we identified YAP WW1 domain p53-binding protein-2 K. S. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). p53BP-2 was isolated as one of two proteins that interact with the protein, not with a in a yeast two-hybrid K. S. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). In the point of in interaction are located in the domain S. Science. 1996; 274: PubMed Scopus Google Scholar). p53BP-2, composed of amino possesses a motif, and one SH3 domain at the carboxyl-terminal end A). the two-hybrid and has that the and the SH3 domain of p53BP-2 interact with the domain of the interaction between and K. S. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar, S. Science. 1996; 274: PubMed Scopus Google Scholar). The p53BP-2 SH3 domain not interact with a PXXP or PXXDY consensus motif. p53BP-2 is of a protein has that p53BP-2 can also interact with protein and protein FEBS Lett. 1995; PubMed Scopus Google Scholar, Mol. Biol. 1996; 16: PubMed Google Scholar, M. N. T. Kato H. T. 1999; 18: PubMed Scopus Google Scholar, H. K. M. T. 2000; Google Scholar). These interactions are and can by that the interaction between p53BP-2 and YAP is on the presence of the YAP WW1 and p53BP-2 SH3 the the binding motifs of two domains were The p53BP-2 YPPPPY sequence was for interaction with the YAP WW1 domain, and the YAP bound to the p53BP-2 SH3 domain. The unusual SH3 domain-binding motif to due to the presence of three consecutive tryptophans within the βC of the SH3 domain. By we that YAP was a factor and that the interaction between YAP and p53BP-2 in In addition, overexpression of a constitutively active form of c-Yes or also that this phosphorylation might decrease or the binding between YAP and The was with a from the from in which were into the at the using were into the which to a the sequence between and was and are in and the and are of interactions was in the which to the the as the was by to the domain of from the into the is the domain expression is the and to the for the YAP WW1 domain acids (2Chen H.I. Sudol M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7819-7823Crossref PubMed Scopus (486) Google Scholar). The is the with the H.I. Einbond A. Linn H. E. S. Sudol M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). is the domain expression possesses the of YAP, which to the that for the first we a acids to of the with the was to the motif of acids (2Chen H.I. Sudol M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7819-7823Crossref PubMed Scopus (486) Google Scholar). was by by of p53BP-2 into the at the by To the we the and the motif acids of p53BP-2 X. Sudol M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). to to with a point were by using the and the the point mutation and the The were into at the and and were by using the and the on p53BP-2 The was into at and the of p53BP-2 acids to the of the of into the at and and were from the by and with by the was the between amino acids and of to the in which the was by the from the and the was by of by the from the and the was the as the of the into the we the to the of YAP into the at the and an was from the by and with of I and to the in which the point mutation was by the the using a is the sequence of p53BP-2 into the at the and The and to the sequence of c-Yes and into of the from of The the of the containing five binding for were in containing and at in a were in using the as X. S. C. G. G. 1998; 17: PubMed Scopus Google Scholar). The protein of was by the protein we the of protein, which was to the with the protein followed the for we 1 of D. Full Text PDF PubMed Scopus Google The were with of the protein for in the presence of of 1 and and of to the of to P. M. Full Text PDF PubMed Scopus Google Scholar). were with different into the The proteins were by 1 for at proteins were and on as X. Sudol M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). were in and in the presence of the by were in 1 and with and at for with protein bound to The were three with p53BP-2 from amino acids to as a protein was by using the and the of this were on by from the and on The protein of the was and to for into and were and on of to as M. H. Mol. Biol. PubMed Scopus Google Scholar). in and were on and to were for 1 at in and with or the M. 1994; Google and from were 1 were with the The were for 1 at with or of the we the from were in of protein were with for 1 at and protein were and for 1 The were with and with The for proteins a protein kinase A proteins were with by protein kinase A from to the X. Sudol M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). were on a by Scopus Google Scholar, Scopus Google Scholar). The were in and for at proteins were to the for at were with were at were in for 1 at proteins were in the at were with To understand the of YAP, we for protein partners that interact with its interaction the WW1 domain. the first located WW domain of YAP this domain is in the two of In we isolated two proteins and that interacted in vitro with the YAP WW1 domain (2Chen H.I. Sudol M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7819-7823Crossref PubMed Scopus (486) Google Scholar). To the of other proteins interact with the WW1 domain of YAP, on using protein were and the which is known to the domain for binding to H.I. Einbond A. Linn H. E. S. Sudol M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google were on the proteins were to and with in there were major proteins of and kDa that were from by the YAP WW1 domain. of the were by from and protein not To binding partners of the YAP WW1 domain that were in the in a yeast two-hybrid was A was with the YAP WW1 domain as that were on and in a were The were the acids acids the protein with a an sequence an and p53BP-2 acids which was isolated the of p53BP-2, of the isolated the PPXY motif for binding to the WW1 domain of In addition, the of for the consensus sequence that as a core for an motif for binding to the WW1 domain of the of p53BP-2, we the as In addition, of p53BP-2 with its the (i) the of G. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google a that the of p53BP-2 containing the motif can interact in vitro with the YAP WW1 domain, and (ii) in vitro at of the core of the YAP WW1 through on H. K.S. S. Sudol M. Biol. Chem. 1997; PubMed Scopus Google Scholar). we have that the containing cores the affinity for the WW1 domain of and YAP H. K.S. S. Sudol M. Biol. Chem. 1997; PubMed Scopus Google Scholar). To the between YAP and p53BP-2, the interaction between and the p53BP-2 proline-rich motif to the domain was In we did the in which was to the domain of whereas the YAP WW1 domain was to the domain in the motif of p53BP-2 by interact with the YAP WW1 domain in whereas a of the YAP WW 1 domain, and did not interact with the not X. Sudol M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). we and the by and K. S. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google using to the domain and which to the carboxyl-terminal of p53BP-2 from the PPXY motif to the end of the protein acids not To the of p53BP-2 that interacts with YAP, two different proteins of p53BP-2 and were in and the two YAP from whereas the motif of or The was with the motif by is also to is to that has a affinity for YAP for that in can interact with YAP to this complex. Since YAP interacts with the SH3 domain of we that the SH3 domain of p53BP-2 might also interact with To the SH3 domain was by the two β strands of the p53BP-2 SH3 domain from the and the were in the p53BP-2 SH3 domain or with YAP the of the was with that of the To the SH3 domain of p53BP-2 interacts with YAP that the sequence of YAP with amino acids between two consecutive were The were to a through their as in the Scopus Google Scholar). The was with the protein containing the SH3 domain of in the p53BP-2 SH3 domain bound to YAP through two and whereas the did not interact with as not and the which did not the general consensus sequence PXXP or PXXDY for binding to SH3 we also the which was to bind to the p53BP-2 SH3 domain S. Science. 1996; 274: PubMed Scopus Google and two and that were identified in a as to the Src and p53BP-2 SH3 domains, Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). we of the with a point mutation to the PXXP motif. In addition, a mutation within the was mutation was to the S. Science. 1996; 274: PubMed Scopus Google Scholar). in the motif did not interact with the p53BP-2 SH3 domain, whereas the binding for p53BP-2 and the were in this binding the affinity of the p53BP-2 SH3 domain for YAP was that for in from the and the the point mutation in the sequence this the mutation in the motif did and only a decrease was that the p53BP-2 SH3 domain interacts with a binding motif in which amino acids to To the binding motif for the p53BP-2 SH3 domain, and on the YAP sequence were using the in the sequence for the interaction between the SH3 domain of p53BP-2 and YAP was the VPMRLR that the bound a point mutation the interaction with the p53BP-2 SH3 domain, reminiscent of the that the amino acid at this for By of SH3 domain in the two amino acid were identified that might the SH3 domain of p53BP-2 not the PXXP or PXXDY motif to bind to YAP, the VPMRLR core as its the SH3 domain of p53BP-2 is in three tryptophans in a located in the βC strand for a the SH3 domain of p53BP-2 not have the consensus tyrosine aromatic amino within the the is also observed in the sequence of the SH3 domain of which interacts with a binding motif, the PXXDY and the of for SH3 domains (13Mongiovi A.M. Romano P.R. Panni S. Mendoza M. Wong W.T. Musacchio A. Cesarini G. Di Fiore P.P. EMBO J. 1999; 18: 5300-5309Crossref PubMed Scopus (155) Google Scholar). To the role of two in the binding of the SH3 domain of p53BP-2, point in the βC and strands were this we to and to and within the the p53BP-2 SH3 was by due to the that amino acids are at this in other SH3 domains The binding of were by the in the as as the interacted with SH3 domain-binding of YAP to as In bound to a in which a PXXP motif The to the which bound as as the for the presence of the PXXP motif. The mutation in the motif the interaction with the three SH3 domain as as with the mutation to Group II of SH3 domains the three interacted with the PXXDY or motif not In that a binding for SH3 domains, as represented by the SH3 domain of p53BP-2, by the consecutive within the βC strand of the domain. that the SH3 domain of p53BP-2 a of for SH3 domains acid of SH3 is a of SH3 the of p53BP-2 β amino acids are in amino acids are in The is to the two major between the p53BP-2 SH3 domain and other SH3 within the p53BP-2 SH3 domain is for binding to SH3 domain-binding motifs. with different and The of the three are amino acids the within the is a of SH3 the of p53BP-2 β amino acids are in amino acids are in The is to the two major between the p53BP-2 SH3 domain and other SH3 To understand the interaction between the YAP WW1 domain and the p53BP-2 motif, the core and its were the we showed that the the sequence to interact with the WW1 domain of YAP (Fig. A and To the of amino acid in the we an using the binding and the binding the motif are for binding to the YAP WW1 domain (Fig. on only short acids that are to a can we to the consensus sequence with The was by on the proline-rich in the The was to the The were for their to YAP from the consensus sequence in from the consensus sequence by the binding to amino in the proline-rich core of p53BP-2 for the YAP Since the proteins, on and with YAP WW1 domain, the consensus sequence as that in the binding not we that the observed between and the in of the binding on the whereas for the binding in The to to the that motif is the sequence for the YAP WW1 interaction in Since p53BP-2 is a protein M. N. T. Kato H. T. 1999; 18: PubMed Scopus Google and YAP is in the and the (15Mohler P.J. Kreda S.M. Boucher R.C. Sudol M. Stutts M.J. Milgram S.L. J. Cell Biol. 1999; 147: 879-890Crossref PubMed Scopus (166) Google Scholar, Chen K. EMBO J. 1999; 18: PubMed Scopus Google two proteins interact in and Chen K. EMBO J. 1999; 18: PubMed Scopus Google have that YAP a domain within its carboxyl-terminal decided to this and a as a for the YAP·p53BP-2 complex. The domain of was to YAP and with a containing the of five in the expression in a was on the domain of YAP its within the did not to a the overexpression of did not In the we p53BP-2 also possesses in p53BP-2 to the domain of did not the of that p53BP-2 not The of and to which was for YAP not that two proteins interact in The with different of p53BP-2 did not modify the of by (Fig. the interaction of p53BP-2 and YAP in only the carboxyl-terminal of p53BP-2 was in of by the of p53BP-2 p53BP-2 proteins might due to the of p53BP-2, as M. N. T. Kato H. T. 1999; 18: PubMed Scopus Google Scholar). the of binding between YAP and p53BP-2 was on the presence of the WW and SH3 domains (Fig. and Since YAP was first as a protein, we the of overexpression on the interaction between YAP and To the the of the kinase a constitutively active form of c-Yes the was also The of the with the to a decrease in in a whereas the did not the of A). Since the did not the of we that the kinase of the affinity between YAP and The were with a constitutively active Src not that at two non-receptor tyrosine and can or the interaction between YAP and Since non-receptor tyrosine kinases the binding affinity between YAP and p53BP-2, we the tyrosine phosphorylation of p53BP-2, that YAP is not a a phosphoserine protein M. 1994; Google Scholar). in p53BP-2 was on its the active of not the was that non-receptor tyrosine kinases can p53BP-2 or Since the motif of p53BP-2 possesses amino acids the of their phosphorylation on binding affinity were were also the in the of the the tyrosine or or in was by its by an amino acid to the or by a amino acid in of by or other amino acid the binding of the YAP WW1 domain. the the binding to the WW1 domain, whereas the or of did not the the phosphorylation of or did not to modify the whereas of two with of the Since we not which is in only that the interaction between YAP and p53BP-2 negatively by In this we identified a of showed that this interaction in vitro vivo as by and yeast and two-hybrid we to two proteins, YAP and p53BP-2 by their not The other on p53BP-2 have not to with this protein K. S. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar, FEBS Lett. 1995; PubMed Scopus Google Scholar, Mol. Biol. 1996; 16: PubMed Google Scholar, M. N. T. Kato H. T. 1999; 18: PubMed Scopus Google Scholar). to their one the of p53BP-2 M. N. T. Kato H. T. 1999; 18: PubMed Scopus Google Scholar). In the in the by or also by the p53BP-2 (Fig. we other as p53BP-2 in different of the to a YAP and p53BP-2 A of p53BP-2 its SH3 domain and a binding motif of the motif the observed in between and is a motif to the YAP is in the of acids to that an interaction between YAP and p53BP-2 the YAP WW1 and p53BP-2 SH3 By and we have that the PPXY binding motif, by is not for an interaction with the YAP WW1 domain. In the p53BP-2 the YAP WW1 domain the to interact with a is in binding a factor that also binds to YAP Chen K. EMBO J. 1999; 18: PubMed Scopus Google Scholar). A using the sequence showed that other proteins this motif, as the factor that proteins also interact with the YAP WW1 domain or WW is in with multiple protein observed in the with the YAP WW1 domain (Fig. is to that p53BP-2 was also by was not one of the major in not The that p53BP-2 did not as a major in this that SH3 and WW domains are for a and interaction only the WW1 domain of YAP the was in the The of other partners to understand the of the WW motif the p53BP-2 SH3 domain binds to YAP the VPMRLR a SH3 domain-binding motif or The of the tryptophan by an arginine in the βC the SH3 domain from interacting with a binding motif. that the presence of three tryptophans three aromatic amino in a within the βC is for the SH3 domain interaction with a binding motif. is not in to the consensus binding motif of the p53BP-2 SH3 domain by Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google this consensus sequence was from a in which the PXXP motif was To to with a on the as as the also to the to the other SH3 domains three aromatic in a have that the c-Yes kinase to p53BP-2 tyrosine phosphorylation and to a of the binding affinity between YAP and the carboxyl-terminal of we that tyrosine phosphorylation of the motif can and or binding to the YAP WW1 domain (Fig. a by tyrosine that the activated by non-receptor tyrosine kinases might also we showed that the phosphorylation within the motif the interaction with the YAP WW1 domain. to which amino is in vivo and to to the of c-Yes overexpression on the YAP·p53BP-2 complex. to as not of the YAP·p53BP-2 of the (i) The p53BP-2 SH3 domain is for its interaction with YAP and and (ii) in a yeast we to a not that there a between YAP and for binding to p53BP-2, as has with the other partners of p53BP-2 K. S. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar, FEBS Lett. 1995; PubMed Scopus Google Scholar, Mol. Biol. 1996; 16: PubMed Google Scholar, M. N. T. Kato H. T. 1999; 18: PubMed Scopus Google Scholar). The role of p53BP-2 is propose that p53BP-2 is a protein M. N. T. Kato H. T. 1999; 18: PubMed Scopus Google whereas that p53BP-2 overexpression not to Mol. Biol. 1996; 16: PubMed Google Scholar). due to the by the a between the of non-receptor tyrosine kinases and the of p53BP-2 from its binding with YAP, p53BP-2 to regulate and Linn for of the for the and and and for on the Yes-associated protein WW domain-binding protein p53-binding protein-2 chloramphenicol acetyltransferase/enzyme-linked immunosorbent protein kinase