The ERBB2/HER2 Receptor Differentially Interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 Domain Proteins

Identification of protein complexes associated with the ERBB2/HER2 receptor may help unravel the mechanisms of its activation and regulation in normal and pathological situations. Interactions between ERBB2/HER2 and Src homology 2 or phosphotyrosine binding domain signaling proteins have been extensively studied. We have identified ERBIN and PICK1 as new binding partners for ERBB2/HER2 that associate with its carboxyl-terminal sequence through a PDZ (PSD-95/DLG/ZO-1) domain. This peptide sequence acts as a dominant retention or targeting basolateral signal for receptors in epithelial cells. ERBIN belongs to the newly described LAP (LRR and PDZ) protein family, whose function is crucial in non vertebrates for epithelial homeostasis. Whereas ERBIN appears to locate ERBB2/HER2 to the basolateral epithelium, PICK1 is thought to be involved in the clustering of receptors. We show here that ERBIN and PICK1 bind to ERBB2/HER2 with different mechanisms, and we propose that these interactions are regulated in cells. Since ERBIN and PICK1 tend to oligomerize, further complexity of protein networks may participate in ERBB2/HER2 functions and specificity. Identification of protein complexes associated with the ERBB2/HER2 receptor may help unravel the mechanisms of its activation and regulation in normal and pathological situations. Interactions between ERBB2/HER2 and Src homology 2 or phosphotyrosine binding domain signaling proteins have been extensively studied. We have identified ERBIN and PICK1 as new binding partners for ERBB2/HER2 that associate with its carboxyl-terminal sequence through a PDZ (PSD-95/DLG/ZO-1) domain. This peptide sequence acts as a dominant retention or targeting basolateral signal for receptors in epithelial cells. ERBIN belongs to the newly described LAP (LRR and PDZ) protein family, whose function is crucial in non vertebrates for epithelial homeostasis. Whereas ERBIN appears to locate ERBB2/HER2 to the basolateral epithelium, PICK1 is thought to be involved in the clustering of receptors. We show here that ERBIN and PICK1 bind to ERBB2/HER2 with different mechanisms, and we propose that these interactions are regulated in cells. Since ERBIN and PICK1 tend to oligomerize, further complexity of protein networks may participate in ERBB2/HER2 functions and specificity. receptor with tyrosine kinase activity PSD-95/DLG/ZO-1 Src homology 2 ERBB2-interacting protein LRR and PDZ human neurotrophin receptor P75 Madin-Darby canine kidney glutathione S-transferase nitric-oxide synthase epidermal growth factor epidermal growth factor receptor 3-aminotriazole Tris-buffered saline binding domain activation domain ephrin receptor The ERBB2/HER-2 gene is overexpressed in about 30% of human breast cancers and is also frequently altered in carcinoma of lungs and kidneys. The ERBB2 protein belongs to the large family of receptors with tyrosine kinase activity (RTK)1 and more precisely to the ERBB subfamily of four receptors which includes the EGF receptor. Upon dimerization and activation, it phosphorylates many substrates including itself. This step induces a network of protein interactions. For example, phosphotyrosine binding and SH2 domains found in cytosolic proteins such as GRB2 and SHC adaptors bind to phosphorylated ERBB2 and lead to the activation of the RAS pathway (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4594) Google Scholar, 2Pawson T. Scott J.D. Science. 1997; 278: 2075-2080Crossref PubMed Scopus (1891) Google Scholar). RTKs also interact with cytoplasmic proteins in a non-phosphorylated dependent manner by means of PDZ protein modules found in adaptor proteins (3Simske J.S. Kaech S.M. Harp S.A. Kim S.K. Cell. 1996; 85: 195-204Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 4Hock B. Bohme B. Karn T. Yamamoto T. Kaibuchi K. Holtrich U. Holland S. Pawson T. Rubsamen-Waigmann H. Strebhardt K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9779-9784Crossref PubMed Scopus (174) Google Scholar, 5Torres R. Firestein B.L. Dong H. Staudinger J. Olson E.N. Huganir R.L. Bredt D.S. Gale N.W. Yancopoulos G.D. Neuron. 1998; 21: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar, 6Borg J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar, 7Garcia R.A. Vasudevan K. Buonanno A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3596-3601Crossref PubMed Scopus (243) Google Scholar, 8Huang Y.Z. Won S. Ali D.W. Wang Q. Tanowitz M. Du Q.S. Pelkey K.A. Yang D.J. Xiong W.C. Salter M.W. Mei L. Neuron. 2000; 26: 443-455Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). PDZ domains are 90–100-amino acid domains that interact with short peptides usually found at the carboxyl terminus of proteins. Proteins bearing a S/TXV motif, such as the glutamate receptors (NMDAR) and K+ channels, interact with class I PDZ domains found in LIN-7 and PSD-95 (9Songyang Z. Fanning A.S. Fu C. Xu J. Marfatia S.M. Chishti A.H. Crompton A. Chan A.C. Anderson J.M. Cantley L.C. Science. 1997; 275: 73-77Crossref PubMed Scopus (1212) Google Scholar, 10Fanning A.S. Anderson J.M Curr. Top. Microbiol. Immunol. 1998; 228: 209-233PubMed Google Scholar). The second class of PDZ domains including the LIN-2/CASK PDZ domain prefers a carboxyl-terminal ΨXΨ sequence, where Ψ is a hydrophobic residue. A third class of PDZ domain including the NOS PDZ domain binds to DXV peptides and PDZ domains (11Brenman J.E. Chao D.S. Gee S.H. McGee A.W. Craven S.E. Santillano D.R. Wu Z. Huang F. Xia H. Peters M.F. Froehner S.C. Bredt D.S. Cell. 1996; 84: 757-767Abstract Full Text Full Text PDF PubMed Scopus (1437) Google Scholar, 12Stricker N.L. Christopherson K.S. Yi B.A. Schatz P.J. Raab R.W. Dawes G. Bassett Jr, D.E. Bredt D.S. Li M. Nat. Biotechnol. 1997; 15: 336-342Crossref PubMed Scopus (218) Google Scholar). Within the RTK superfamily, several members have a canonical PDZ domain binding site in carboxyl-terminal position, i.e. two ERBB receptors (ERBB2/HER2 and ERBB4/HER4), MUSK (a muscle-specific receptor), and several EPH receptor family members involved in developmental processes such as axon guidance. Kim and colleagues have demonstrated the importance of PDZ domain proteins for RTKs function in nonvertebrates. LET-23, the homolog of ERBB receptors in C. elegans, is localized to the basolateral epithelial membrane upon interaction with LIN-7, a PDZ protein that associates with LIN-2 and LIN-10, two other PDZ domain proteins (3Simske J.S. Kaech S.M. Harp S.A. Kim S.K. Cell. 1996; 85: 195-204Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 13Kaech S.M. Whitfield C.W. Kim S.K. Cell. 1998; 94: 761-771Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). The LIN-7/LIN-2/LIN-10 complex is crucial for proper LET-23 function in insuring a basolateral localization of LET-23 molecules in epithelial cells. Subsequent work has inferred that a subset of mammalian EPH receptors are recruited to in by and two PDZ proteins B. Bohme B. Karn T. Yamamoto T. Kaibuchi K. Holtrich U. Holland S. Pawson T. Rubsamen-Waigmann H. Strebhardt K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9779-9784Crossref PubMed Scopus (174) Google Scholar, 5Torres R. Firestein B.L. Dong H. Staudinger J. Olson E.N. Huganir R.L. Bredt D.S. Gale N.W. Yancopoulos G.D. Neuron. 1998; 21: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar). adaptors are also for the tyrosine kinase activity of and may participate in ERBB family is a binding for a kinase also associated with K+ and in R.A. Vasudevan K. Buonanno A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3596-3601Crossref PubMed Scopus (243) Google Scholar, 8Huang Y.Z. Won S. Ali D.W. Wang Q. Tanowitz M. Du Q.S. Pelkey K.A. Yang D.J. Xiong W.C. Salter M.W. Mei L. Neuron. 2000; 26: 443-455Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). is thought that these PDZ interactions proteins to and participate to signaling For example, PSD-95 have to a in signaling M. M. L.C. M. M.F. 1998; PubMed Scopus Google Scholar). of RTKs including growth factor a for and for are also regulated by with and other PDZ proteins including K. J. A. R. Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. J.M. J. J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, D. G.D. Z. Pawson T. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). ERBB2/HER2 a PDZ domain binding site in its carboxyl terminus and we ERBIN a PDZ domain as a for the receptor in J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). ERBB2/HER2 binding we a by the and identified a second for ERBB2/HER2 PICK1 is a PDZ domain protein described as for J. J. R. Olson E.N. J. Cell Biol. PubMed Scopus Google Scholar). PICK1 is thought to as a protein to receptors and of signaling or targeting at in J. Staudinger J. Huganir R.L. Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar). We show by the and in that PICK1 with PICK1 binds to the found in ERBB2/HER2 in to the PDZ domain is for the PICK1 also with the found in MUSK and two RTKs for the function of ERBIN prefers a in ERBB2/HER2 and proteins to we show that ERBIN has a to through a domain of ERBB2 with with to interact with the receptor. We show that the carboxyl-terminal sequence of ERBB2/HER2 is a dominant basolateral localization sequence it is to receptor to the basolateral of cells. This that PDZ domain proteins are involved in the regulation of ERBB2/HER2 the in the of ERBB2 or or the of proteins to the which For in which as a by the as a and the the with that and in the and 3-aminotriazole and for the activity by the in the the of in or to for growth in and activity and for with saline and in with and at to by at for further For with at and complexes to with in and by and or as described J.-P. J. E. Margolis B. Cell. Biol. 1996; PubMed Scopus Google Scholar). For the membrane 2 at with proteins with protein kinase A and in with and by and binding as described J.-P. J. E. Margolis B. Cell. Biol. 1996; PubMed Scopus Google Scholar). and in and with to ERBIN to different of the protein in or The to proteins to the J.-P. J. E. Margolis B. Cell. Biol. 1996; PubMed Scopus Google Scholar). The to proteins. the by A as a to a the PDZ domain and PDZ domain between the human and human ERBB2/HER2 or by for the of ERBB2/HER2 or in to the of and The and for and and to and A by a for and as described Bivic A. E. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google a the domain of human and a of Bivic A. K. E. J. Cell Biol. 1990; PubMed Scopus Google Scholar). for and for as described L. A. Chao M. E. Le Bivic A. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). or the by the We have a for ERBB2/HER2 in ERBIN is a PDZ domain protein to the LAP (LRR and PDZ) protein family that includes and J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar, J. 1996; PubMed Google Scholar, D. 2000; PubMed Scopus Google Scholar, Birnbaum D. J.-P. J. E. M. R. B. Nat. Cell Biol. 2000; 7: Scopus Google Scholar, R. A. S. J.M. M. Nat. Cell Biol. 2000; PubMed Scopus Google Scholar). The ERBIN PDZ domain with the carboxyl-terminal in which a We the in to further for for is for the carboxyl-terminal by for the for the and acid in the ERBB2 peptide to for in to to the binding domain the activation domain to the ERBIN PDZ domain by the of to of with and to a of the carboxyl-terminal and of the in ERBB2 the interaction with ERBIN J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). also altered in position, in position, in position, and in We ERBB2 and in and receptors with a PDZ domain in a of the acid in position, in position, and tyrosine in to as as of ERBB2 the binding to the ERBIN PDZ domain. found in to of the interaction in the with the This may that is as crucial for interaction in further the ERBIN PDZ domain binding we a to the interaction of domain with peptides found in the carboxyl terminus of receptors and for and are for PDZ acid peptides to the and of proteins by The membrane with a and the membrane for to proteins. signal found we a or PDZ domain as a the ERBIN PDZ domain with ERBB2 with other human family members to the LET-23 the other proteins the carboxyl of and with ERBIN these peptides have sequence to the ERBB2 peptide at the crucial found for ERBIN a carboxyl-terminal in or and hydrophobic in and or a or these that the ERBIN PDZ domain binds to a where Ψ hydrophobic and We in for other mammalian proteins such a and found the proteins in including a a and a for and protein are binding partners for a ERBIN with has been to bind PDZ domain proteins T. M. K. H. T. 1998; PubMed Scopus Google Scholar). of and show that PDZ domains two and A. J. Kim E. M. R. Cell. 1996; 85: Full Text Full Text PDF PubMed Scopus Google Scholar, C. S. F. Marfatia S.M. Chishti A.H. 1996; PubMed Scopus Google Scholar, Anderson J.M. Nat. Biol. 1998; PubMed Scopus Google Scholar). The peptide of receptors binds to the between the second and the second with a a A found in the second for class or for class and for NOS class PDZ a of the found in in the the PSD-95 class I PDZ domain prefers a or in in the peptide and the class PDZ domain hydrophobic in class PDZ domain in NOS binds to in a we identified a the ERBIN PDZ domain the in to as found in which the interaction with ERBB2 J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). The NOS PDZ domain with DXV We the to in ERBB2 interaction found with the ERBIN by the interaction with ERBB2 the ERBIN PDZ domain class I to class This be by the that the NOS PDZ domain the PDZ domain domain N.L. Christopherson K.S. Yi B.A. Schatz P.J. Raab R.W. Dawes G. Bassett Jr, D.E. Bredt D.S. Li M. Nat. Biotechnol. 1997; 15: 336-342Crossref PubMed Scopus (218) Google Scholar). This is in the ERBIN PDZ domain. We also the to as found in class PDZ domain interaction with ERBB2 as in to PDZ domain This in a where ERBB2 more by ERBIN by ERBIN 2 The in ERBB2 binds to the class I ERBIN PDZ it to the ΨXΨ binding site for class PDZ to in ERBIN PDZ domain the binding to the ERBIN PDZ domain binds to the found in We have identified ERBB2 and ERBIN peptide for the interaction between the PDZ domain and its interaction with receptors is a for PDZ For example, the PDZ domain binds to and S. J. 1996; PubMed Google Scholar, Marfatia S.M. Z. Chishti A.H. Anderson J.M. J. Cell Biol. 1998; PubMed Scopus Google Scholar, Yang V. S. M. J. Cell Biol. 1998; PubMed Scopus Google and PSD-95 with glutamate and E. M. A. M. PubMed Scopus Google Scholar, Science. PubMed Scopus Google Scholar, A. A. T. K. T. S. M. K. T. Science. 1996; PubMed Scopus Google Scholar). the other receptors bind different PDZ a class of EPH receptors binds to and PDZ domains B. Bohme B. Karn T. Yamamoto T. Kaibuchi K. Holtrich U. Holland S. Pawson T. Rubsamen-Waigmann H. Strebhardt K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9779-9784Crossref PubMed Scopus (174) Google Scholar, 5Torres R. Firestein B.L. Dong H. Staudinger J. Olson E.N. Huganir R.L. Bredt D.S. Gale N.W. Yancopoulos G.D. Neuron. 1998; 21: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar). We have that the ERBIN PDZ domain in with several peptide it is that ERBB2 binds to other PDZ proteins. for other ERBB2 we a with as a different the PICK1 protein PICK1 is protein PDZ domain and a in its carboxyl PICK1 described as a for EPH more through a PDZ domain interaction R. Firestein B.L. Dong H. Staudinger J. Olson E.N. Huganir R.L. Bredt D.S. Gale N.W. Yancopoulos G.D. Neuron. 1998; 21: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (397) Google J. J. R. Olson E.N. J. Cell Biol. PubMed Scopus Google Scholar, J. Staudinger J. Huganir R.L. Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar, M. B. Neuron. 2000; 26: Full Text Full Text PDF PubMed Scopus Google Scholar). We found binding between PICK1 and ERBB2 the carboxyl-terminal in ERBB2 by further the of PICK1 involved in the we a acid carboxyl-terminal in the protein and to interaction between and a described the PICK1 PDZ domain to also the interaction J. J. Olson E.N. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). in the of NOS PDZ these that the PICK1 PDZ domain is to bind to ERBB2 N.L. Christopherson K.S. Yi B.A. Schatz P.J. Raab R.W. Dawes G. Bassett Jr, D.E. Bredt D.S. Li M. Nat. Biotechnol. 1997; 15: 336-342Crossref PubMed Scopus (218) Google Scholar). we proteins PICK1 PICK1 PICK1 and the PICK1 PDZ domain with and with proteins to proteins and of the membrane with that to of proteins PDZ domain ERBB2 the found we a ERBB2 PICK1 has been described as a binding for other proteins We ERBIN with PICK1 including and R. Firestein B.L. Dong H. Staudinger J. Olson E.N. Huganir R.L. Bredt D.S. Gale N.W. Yancopoulos G.D. Neuron. 1998; 21: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar, J. J. Olson E.N. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The carboxyl-terminal peptide of these proteins to and with PDZ domain or PICK1 in We and and with the two PDZ to which with PICK1 also to and A of ERBB2 with or ERBIN PDZ domain. The interaction the carboxyl-terminal in to ERBIN by other of in to in ERBB2 the interaction with ERBIN or PICK1 We that PICK1 is a new binding for ERBB2 that also with RTK including and we also that ERBIN and PICK1 bind to of PICK1 through its has been J. J. Olson E.N. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). PDZ proteins including PSD-95 and through and domain Kim E. M. Neuron. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, L. J. Biol. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). the we found that ERBIN the ERBIN PDZ domain with with PICK1 and A PDZ domain ERBIN ERBIN of its PDZ interaction found with the or PDZ domain that ERBIN is to through a domain the interaction of PICK1 with ERBB2 in we a of PICK1 with a the of and the of Proteins with and by of the membrane with that PICK1 with the found with of the in ERBB2 the interaction with PDZ domain proteins ERBIN a for ERBB2 kinase activity and to with phosphorylated ERBB2 J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). PICK1 to the receptor and EGF of PICK1 by the that with the protein of ERBIN dependent the ERBB2 kinase activity and interaction with the receptor we found that PICK1 phosphorylated by ERBB2 and that of the PDZ domain binding site in ERBB2 that a PDZ binds to receptors and signaling in the of S. R.A. Cell. Biol. 2000; PubMed Scopus Google Scholar). We found in the of proteins the and ERBB2 involved in its receptors interact with SHC and two of ERBB2 signal EGF is that a subset of including have a tyrosine kinase activity regulated by PDZ proteins S. R.A. Cell. Biol. 2000; PubMed Scopus Google including ERBB2 and have 4Hock B. Bohme B. Karn T. Yamamoto T. Kaibuchi K. Holtrich U. Holland S. Pawson T. Rubsamen-Waigmann H. Strebhardt K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9779-9784Crossref PubMed Scopus (174) Google 6Borg J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google or of the PDZ domain binding site in ERBB2 a of the receptor the basolateral to the in epithelial J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). This may that the of the receptor as a targeting or retention signal to the basolateral more precisely we have the carboxyl terminus of ERBB2 to the described P75 neurotrophin receptor is a protein found at the of in epithelial Bivic A. A. Chao M. E. J. Cell Biol. PubMed Scopus Google Scholar). This localization in the and a membrane of the cytoplasmic of the localization of the protein Bivic A. A. Chao M. E. J. Cell Biol. PubMed Scopus Google Scholar, L. L. Le Bivic A. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). We the of with the of ERBB2 or is a acid to the basolateral through a PDZ domain interaction C. C. A. R. Kaech S.M. E. A. Kim S.K. G. J. PubMed Scopus Google Scholar). of and P75 and of the of receptors at with a protein in and a human Bivic A. K. E. J. Cell Biol. 1990; PubMed Scopus Google Scholar). that with the the of in of or localized to the basolateral membrane and the membrane in Cell the or the basolateral of the and the of the receptors found to the of the basolateral of the of and the the membrane and as Bivic A. A. Chao M. E. J. Cell Biol. PubMed Scopus Google the found in the basolateral membrane and We that the ERBB2 PDZ domain binding site acts as a dominant basolateral localization signal in epithelial cells. ERBB2/HER2 is a of the ERBB RTK subfamily in the of mammalian and a in breast M. 2000; PubMed Scopus Google Scholar). We to ERBB2 binding partners and protein complexes for its proteins involved in ERBB2 signaling such as GRB2 and a PDZ adaptor we is for ERBB2 targeting or retention in J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). This further the interaction between the ERBIN PDZ domain and We have precisely the binding site for the ERBIN PDZ domain and identified a of receptors such are glutamate receptor and and which are binding partners for PSD-95 in the We interaction between the PDZ domain to ERBIN PDZ and these peptides that ERBIN and bind to different receptors. ERBIN is in the and a in receptors. is that ERBIN to the complex associated to receptors H. J.S. Nat. 2000; PubMed Scopus Google Scholar). ERBIN with a LAP four class I PDZ domains in carboxyl terminus and the has a class PDZ domain. protein interaction domains have be to for these PDZ binds to a peptide found in the of human that to a class I PDZ domain binding site S. J.M. Cell. Biol. 2000; PubMed Scopus Google Scholar). human and ERBIN are at the of epithelial where may binding partners J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar, S. J.M. Cell. Biol. 2000; PubMed Scopus Google Scholar). PICK1 is described here as a second PDZ protein binding for the ERBB2 receptor. different we show that PICK1 and ERBIN interact with the receptor in a the ERBIN PDZ domain is for the peptide sequence is in the of The PICK1 PDZ domain is for binding to in ERBB2 that the interaction with of in and the binding to The in ERBB2 is for other PICK1 such as MUSK and such a The in be by a or a as in the of and with ERBB2 tyrosine of the receptor. the binding of PICK1 and to is regulated by a carboxyl-terminal sequence phosphorylated by binds to phosphorylated Xia J. Huganir R.L. J. 2000; PubMed Google Scholar). The tyrosine in ERBB2 carboxyl-terminal sequence in to the of ERBB2 and is a site of This that of interaction J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). may binding of PDZ domain proteins to receptors and lead to more and regulated interactions with or kinase We found that PICK1 is in the the and the in epithelial by other J. J. Olson E.N. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). ERBIN is found at the membrane in J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). PICK1 and ERBIN may be involved in different ERBB2 functions in and participate to different protein PICK1 and ERBIN and the of A step be to unravel the of binding partners for these adaptor proteins and to in to ERBB2 function in normal and pathological situations. A large of for PICK1 have been described that adaptor may be for the function of different of receptors. For example, PICK1 EPH receptors and in the a complex for M. B. Neuron. 2000; 26: Full Text Full Text PDF PubMed Scopus Google Scholar). the interaction between PICK1 and it is to that ERBB2 is found at with MUSK and two other PICK1 partners for R. Firestein B.L. Dong H. Staudinger J. Olson E.N. Huganir R.L. Bredt D.S. Gale N.W. Yancopoulos G.D. Neuron. 1998; 21: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar). it appears that PICK1 may different receptors at and a for The is a where growth and by the receptors at the S. 1998; PubMed Scopus Google Scholar). We that PICK1 to the involved in the or targeting of these receptors in The of ERBIN and PICK1 in ERBB2 signal in to a PDZ protein that signaling S. R.A. Cell. Biol. 2000; PubMed Scopus Google Scholar). the of PDZ domains in ERBB2 is We show here that the ERBB2 peptide sequence involved in PDZ domain interaction is to locate to the basolateral of epithelial cells. This that of peptide basolateral ERBB2 to the membrane in J.-P. Marchetto S. Le Bivic A. Ollendorff V. Jaulin-Bastard F. Saito H. Fournier E. Adélaı̈de J. Margolis B. Birnbaum D. Nat. Cell Biol. 2000; 7: 407-414Crossref Scopus (255) Google Scholar). We the that ERBIN and PICK1 are involved in the localization of ERBB2 at in cells. PDZ proteins participate to protein complexes associated with receptors with tyrosine kinase binding are involved in many of RTK functions that have to be We for the J. S. for the of the G. for the and M. and for the We Margolis for and