The function of PTB domain proteins
1999; Elsevier BV; Volume: 56; Issue: 4 Linguagem: Inglês
10.1046/j.1523-1755.1999.00700.x
ISSN1523-1755
AutoresBen Margolis, Jean‐Paul Borg, Sam Straight, Debra J. Meyer,
Tópico(s)FOXO transcription factor regulation
ResumoThe function of PTB domain proteins. Phosphotyrosine binding (PTB) domains have been identified in a large number of proteins. In proteins like Shc and IRS-1, the PTB domain binds in a phosphotyrosine-dependent fashion to peptides that form a β turn. In these proteins, PTB domains play an important role in signal transduction by growth factor receptors. However, in several other proteins, the PTB domains have been found to participate in phosphotyrosine-independent interactions. The X11 family of proteins contains a PTB domain that binds peptides in a phosphotyrosine-independent fashion. The homologue of X11 in C. elegans is the lin-10 gene, a gene crucial for receptor targeting to the basolateral surface of body wall epithelia. The X11/Lin-10 proteins are found in a complex with two other proteins, Lin-2 and Lin-7, which have also been implicated in basolateral targeting in worm epithelia. This protein complex is also likely to be important in the targeting of cell surface proteins in mammalian neurons and epithelia. The ability of the PTB domain to bind peptides in a phosphotyrosine-dependent and -independent fashion allows this domain to be involved in diverse cellular functions. The function of PTB domain proteins. Phosphotyrosine binding (PTB) domains have been identified in a large number of proteins. In proteins like Shc and IRS-1, the PTB domain binds in a phosphotyrosine-dependent fashion to peptides that form a β turn. In these proteins, PTB domains play an important role in signal transduction by growth factor receptors. However, in several other proteins, the PTB domains have been found to participate in phosphotyrosine-independent interactions. The X11 family of proteins contains a PTB domain that binds peptides in a phosphotyrosine-independent fashion. The homologue of X11 in C. elegans is the lin-10 gene, a gene crucial for receptor targeting to the basolateral surface of body wall epithelia. The X11/Lin-10 proteins are found in a complex with two other proteins, Lin-2 and Lin-7, which have also been implicated in basolateral targeting in worm epithelia. This protein complex is also likely to be important in the targeting of cell surface proteins in mammalian neurons and epithelia. The ability of the PTB domain to bind peptides in a phosphotyrosine-dependent and -independent fashion allows this domain to be involved in diverse cellular functions. Studies over the last decade have elucidated the role of protein–protein interaction domains in a variety of cellular processes[1.Pawson T. Scott J.D. Signaling through scaffold, anchoring, and adaptor proteins.Science. 1997; 278: 2075-2080Crossref PubMed Scopus (1847) Google Scholar]. A large number of intracellular protein–protein interaction domains have been identified to date because of the increase in gene cloning and the use of advanced computer algorithms to search sequence databases[2.Bork P. Schultz J. Ponting C.P. Cytoplasmic signalling domains: The next generation.Trends Biochem Sci. 1997; 22: 296-298Abstract Full Text PDF PubMed Scopus (50) Google Scholar]. These domains include the phosphotyrosine binding (PTB), the PSD-95/Zo-1/discs-large (PDZ), Src homology 2 (SH2), Src homology 3 (SH3), and the tryptophan-capstryptophan (WW) domains. These domains can be defined by their primary sequence homology, their structural similarities, and their binding specificity. These domains are evolutionarily conserved and are often found in proteins containing other protein–protein interaction domains, where they act as molecular adaptors linking proteins into functional complexes. Our group has focused most recently on the function of the PTB domain. As is discussed later in this article, this domain was first identified in proteins involved in tyrosine kinase signal transduction. However, recent studies have shown that these domains are involved in a broad range of cellular functions and, in many cases, bind targets independent of phosphotyrosine. We first identified the PTB domain by screening bacterial expression libraries with tyrosine-phosphorylated growth factor receptors[3.Blaikie P. Immanuel D. Wu J. Li N. Yajnik V. Margolis B. A region in Shc distinct from the SH2 domain can bind tyrosine phosphorylated growth factor receptors.J Biol Chem. 1994; 269: 32031-32034Abstract Full Text PDF PubMed Google Scholar]. This domain has also been termed the phosphotyrosine interaction domain (PID) and was identified simultaneously by two other groups[4.Gustafson T.A. He W. Craparo A. Schaub C.D. O'Neill T.J. Phosphotyrosine-dependent interaction of Shc and IRS-1 with the NPEY motif of the insulin receptor via a novel (non-SH2) domain.Mol Cell Biol. 1995; 15: 2500-2508Crossref PubMed Scopus (314) Google Scholar],[5.Kavanaugh W.M. Williams L.T. An alternative to SH2 domains for binding tyrosine-phosphorylated proteins.Science. 1994; 266: 1862-1865Crossref PubMed Scopus (443) Google Scholar]. Previously we used bacterial expression cloning to identify a large number of SH2 domain proteins[6.Margolis B. Skolnik E.Y. Schlessinger J. The use of tyrosine-phosphorylated proteins to screen bacterial expression libraries for SH2 domains.Methods Enzymol. 1995; 255: 360-369Crossref PubMed Scopus (3) Google Scholar]. SH2 domains bind to phosphotyrosine-containing peptides and control numerous signaling pathways involving tyrosine kinases[7.Mayer B.J. Gupta R. Functions of SH2 and SH3 domains.Curr Top Microbiol Immunol. 1998; 228: 1-22PubMed Google Scholar]. Previous work had identified Shc as a binding partner for activated and tyrosine-phosphorylated growth factor receptors[8.Pelicci G. Lanfrancone L. Grignani F. McGlade J. Cavallo F. Forni G. Nicoletti I. Pawson T. Pelicci P.G. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction.Cell. 1992; 70: 93-104Abstract Full Text PDF PubMed Scopus (1112) Google Scholar]. Shc becomes tyrosine phosphorylated after the activation of a large number of growth factor receptors and oncogenes[9.McGlade J. Cheng A. Pelicci G. Pelicci P.G. Pawson T. Shc proteins are phosphorylated and regulated by the v-Src and v-Fps protein-tyrosine kinases.Proc Natl Acad Sci USA. 1992; 89: 8869-8873Crossref PubMed Scopus (235) Google Scholar]. Once phosphorylated, Shc can bind to the Grb2/SOS complex leading to the activation of Ras[10.Rozakis-Adcock M. McGlade J. Mbamalu G. Pelicci G. Daly R. Li W. Batzer A. Thomas S. Brugge J. Pelicci P.G. Schlessinger J. Pawson T. Association of the Shc and Grb2/Sem5, SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.Nature. 1992; 360: 689-692Crossref PubMed Scopus (814) Google Scholar]. Although Shc contains a PTB domain and an SH2 domain, our work and that of others indicated that the PTB domain of Shc was crucial for its interaction with tyrosine-phosphorylated growth factor receptors and oncogenes[11.Blaikie P.A. Fournier E. Dilworth S.M. Birnbaum D. Borg J.P. Margolis B. The role of the Shc phosphotyrosine interaction/phosphotyrosine binding domain and tyrosine phosphorylation sites in polyoma middle T antigen-mediated cell transformation.J Biol Chem. 1997; 272: 20671-20677Crossref PubMed Scopus (27) Google Scholar, 12.Isakoff S.J. Yu Y.-P. Su Y.-C. Blaikie P. Yajnik V. Rose E. Weidner K.M. Sachs M. Margolis B. Skolnik E.Y. The Shc PTB/PI domain is required for Shc tyrosine phosphorylation by the insulin receptor (IR) and recognizes an NPXY motif on the IR that is distinct from IRS-1 in vivo.J Biol Chem. 1996; 271: 3959-3962Crossref PubMed Scopus (56) Google Scholar, 13.Giorgetti-Peraldi S. Ottinger E. Wolf G. Ye B. Burke Jr, Tr Shoelson S.E. Cellular effects of phosphotyrosine-binding domain inhibitors on insulin receptor signaling and trafficking.Mol Cell Biol. 1997; 17: 1180-1188Crossref PubMed Scopus (34) Google Scholar]. The peptide ligand for the Shc PTB domain has been found to be the sequence ψXNPXpY where ψ is a hydrophobic residue, N is asparagine, P is proline, and pY is phosphotyrosine Figure 1[14.Borg J.P. Margolis B.L. Function of PTB domains.Curr Top Microbiol Immunol. 1998; 228: 23-38PubMed Google Scholar]. SH2 domain binding specificity is determined by residues carboxy terminal to the phosphotyrosine, whereas PTB domain specificity is determined by residues amino terminal to the phosphotyrosine. This ψXNPXY motif forms a β turn that is important for interactions with the Shc PTB domain. Site-directed mutagenesis and structural studies have identified the crucial residues of the Shc PTB domain essential for interaction with this ψXNPXpY motif[15.Yajnik V. Blaikie P. Bork P. Margolis B. Identification of residues within the Shc phosphotyrosine binding/phosphotyrosine interaction domain crucial for phosphopeptide interaction.J Biol Chem. 1996; 271: 1813-1816Crossref PubMed Scopus (37) Google Scholar],[16.Zhou M.M. Ravichandran K.S. Olejniczak E.F. Petros A.M. Meadows R.P. Sattler M. Harlan J.E. Wade W.S. Burakoff S.J. Fesik S.W. Structure and ligand recognition of the phosphotyrosine binding domain of Shc.Nature. 1995; 378: 584-592Crossref PubMed Scopus (316) Google Scholar]. These studies have identified residues that are necessary for binding to the phosphotyrosine as well as residues that are crucial for binding to residues amino terminal to the phosphotyrosine. The structure of the Shc PTB domain is highly related to the structure of the pleckstrin homology (PH) domain, a domain that has been shown to bind to phospholipid head group[17.Lemmon M.A. Ferguson K.M. Schlessinger J. PH domains: Diverse sequences with a common fold recruit signaling molecules to the cell surface.Cell. 1996; 85: 621-624Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar]. Studies have suggested that the Shc PTB domain can interact with both phosphotyrosine-containing residues as well as phospholipids, and that both of these binding activities may be essential for Shc function[18.Ravichandran K.S. Zhou M.M. Pratt J.C. Harlan J.E. Walk S.F. Fesik S.W. Burakoff S.J. Evidence for a requirement for both phospholipid and phosphotyrosine binding via the Shc phosphotyrosine-binding domain in vivo.Mol Cell Biol. 1997; 17: 5540-5549Crossref PubMed Google Scholar]. However, the Shc PTB domain interacts with phospholipids and peptides at distinct sites on its surface. Coincident with the identification of the Shc PTB domain, a PTB domain was identified in the insulin receptor substrate (IRS) family of proteins Figure 2[4.Gustafson T.A. He W. Craparo A. Schaub C.D. O'Neill T.J. Phosphotyrosine-dependent interaction of Shc and IRS-1 with the NPEY motif of the insulin receptor via a novel (non-SH2) domain.Mol Cell Biol. 1995; 15: 2500-2508Crossref PubMed Scopus (314) Google Scholar],[19.Sun X.J. Wang L.-M. Zhang Y. Yenush L. Myers M.G. Glasheen E. Lane W.S. Pierce J.H. White M.F. Role of IRS-2 in insulin and cytokine signalling.Nature. 1995; 377: 173-177Crossref PubMed Scopus (751) Google Scholar]. IRS proteins are docking molecules that once tyrosine phosphorylated, bind multiple signaling proteins containing SH2 domains[20.White M.F. The IRS-signalling system: A network of docking proteins that mediate insulin action.Mol Cell Biochem. 1998; 182: 3-11Crossref PubMed Scopus (617) Google Scholar]. The IRS PTB domains have little sequence homology with the Shc PTB domain. Nonetheless, the IRS and Shc PTB domains fold into a similar structure and have similar but not identical binding specificities Figure 1[21.Eck M.J. Dhe Paganon S. Trub T. Nolte R.T. Shoelson S.E. Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor.Cell. 1996; 85: 695-705Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 22.Zhou M.M. Huang B. Olejniczak E.T. Meadows R.P. Shuker S.B. Miyazaki M. Trub T. Shoelson S.E. Fesik S.W. Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain.Nat Struct Biol. 1996; 3: 388-393Crossref PubMed Scopus (107) Google Scholar, 23.Wolf G. Trub T. Ottinger E. Groninga L. Lynch A. White M.F. Miyazaki M. Lee J. Shoelson S.E. PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities.J Biol Chem. 1995; 270: 27407-27410Crossref PubMed Scopus (205) Google Scholar]. There are data to suggest that the PTB domain is crucial for receptor interactions by the IRS proteins, but these data are not as strong as that obtained for the Shc PTB domain[24.Sharma P.M. Egawa K. Gustafson T.A. Martin J.L. Olefsky J.M. Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes.Mol Cell Biol. 1997; 17: 7386-7397Crossref PubMed Scopus (64) Google Scholar]. In IRS proteins, additional domains, including the PH domain, appear important for the coupling of IRS proteins to insulin signaling[24.Sharma P.M. Egawa K. Gustafson T.A. Martin J.L. Olefsky J.M. Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes.Mol Cell Biol. 1997; 17: 7386-7397Crossref PubMed Scopus (64) Google Scholar, 25.Yenush L. Makati K.J. Smithhall J. Ishibashi O. Myers M.G. White M.F. The pleckstrin homology domain is the principle link between insulin receptor and IRS-1.J Biol Chem. 1996; 271: 24300-24306Crossref PubMed Scopus (140) Google Scholar, 26.Sawka-Verhelle D. Tartare-Deckert S. White M.F. Van Obberghen E. Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591–786.J Biol Chem. 1996; 271: 5980-5983Crossref PubMed Scopus (150) Google Scholar]. Recently, other tyrosine kinases substrates have been proposed to have PTB domains related to the IRS PTB domains. These proteins are the downstream of kinase (Dok) and fibroblast growth factor receptor substrate-2 (FRS-2) family of proteins[27.Yamanashi Y. Baltimore D. Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok.Cell. 1997; 88: 205-211Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 28.Carpino N. Wisniewski D. Strife A. Marshak D. Kobayashi R. Stillman B. Clarkson B. p62 (dok): A constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells.Cell. 1997; 88: 197-204Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 29.Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway.Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar]. FRS-2 (also known as SNT) is a tyrosine-phosphorylated docking protein downstream of fibroblast growth factor receptors and nerve growth factor receptors[29.Kouhara H. Hadari Y.R. Spivak-Kroizman T. Schilling J. Bar-Sagi D. Lax I. Schlessinger J. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway.Cell. 1997; 89: 693-702Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar],[30.Xu H. Lee K.W. Goldfarb M. Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adaptor proteins.J Biol Chem. 1998; 273: 17987-17990Crossref PubMed Scopus (141) Google Scholar]. Doks are tyrosine phosphorylated by a large number of tyrosine kinases and were first identified via their interaction with p190 Ras GAP[27.Yamanashi Y. Baltimore D. Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok.Cell. 1997; 88: 205-211Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar],[28.Carpino N. Wisniewski D. Strife A. Marshak D. Kobayashi R. Stillman B. Clarkson B. p62 (dok): A constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells.Cell. 1997; 88: 197-204Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar]. The sequences of the PTB domains of Dok and FRS-2 proteins are highly related to each other but have weak similarity to the IRS PTB domains. The structural and functional relationship between the IRS and Shc PTB domains and the FRS-2 and Dok PTB domains is unclear. Initial studies indicate that the FRS-2 PTB domain is not involved in phosphotyrosine-dependent interactions but is important for FRS-2 coupling to growth factor receptors[30.Xu H. Lee K.W. Goldfarb M. Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adaptor proteins.J Biol Chem. 1998; 273: 17987-17990Crossref PubMed Scopus (141) Google Scholar]. Our group and others have identified several proteins with PTB domains that have sequence homology to the Shc PTB domain[31.Bork P. Margolis B. A phosphotyrosine interaction domain.Cell. 1995; 80: 693-694Abstract Full Text PDF PubMed Scopus (169) Google Scholar]. Some of these proteins are displayed schematically in Figure 2. We had first hypothesized that these proteins would also signal downstream of tyrosine kinases, but this has not proved to be the case. In fact, these proteins appear to be involved in a broad range of cellular functions. One protein, Ced-6[32.Liu Q.A. Hengartner M.O. Candidate adaptor protein CED-6 promotes the engulfment of apoptotic cells in C. elegans.Cell. 1998; 93: 961-972Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar], has been shown to be important for the phagocytosis of apoptotic cells in Caenorhabditis elegans, while another protein, Numb, is crucial for cell fate determination in Drosophila[33.Uemura T. Shepherd S. Ackerman L. January L.Y. January Y.N. Numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos.Cell. 1989; 58: 349-360Abstract Full Text PDF PubMed Scopus (393) Google Scholar]. X11 appears to have an important role in protein trafficking (discussed later in this article), while the function of FE65 is unclear. Capon is a protein that may affect the localization of neuronal nitric oxide synthase[34.Jaffrey S.R. Snowman A.M. Eliasson M.J. Cohen N.A. Snyder S.H. CAPON: A protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95.Neuron. 1998; 20: 115-124Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar]. Disabled has an important role in neuronal development in both flies and mammals[35.Gertler F.B. Hill K.K. Clark M.J. Hoffmann F.M. Dosage-sensitive modifiers of Drosophila abl tyrosine kinase function: Prospero, a regulator of axonal outgrowth, and disabled, a novel tyrosine kinase substrate.Genes Dev. 1993; 7: 441-453Crossref PubMed Scopus (110) Google Scholar],[36.Howell B.W. Hawkes R. Soriano P. Cooper J.A. Neuronal position in the developing brain is regulated by mouse disabled-1.Nature. 1997; 389: 733-737Crossref PubMed Scopus (595) Google Scholar]. Finally, the Jip-1 protein is a scaffolding protein involved in the activation of the Jun kinase (JNK)[37.Whitmarsh A.J. Cavanagh J. Tournier C. Yasuda J. Davis R.J. A mammalian scaffold complex that selectively mediates MAP kinase activation.Science. 1998; 281: 1671-1674Crossref PubMed Scopus (573) Google Scholar]. The discussion of all of these different PTB domain proteins is beyond the scope of this article; here we focus on some of our recent results that have examined the role of PTB domains in cell biology. One major finding of recent studies on PTB domains is that their binding is often independent of phosphotyrosine. This conclusion comes from a variety of studies. First, earlier studies indicated that both the Shc and IRS PTB domains displayed some binding affinity for proteins independent of phosphotyrosine[38.Charest A. Wagner J. Jacob S. McGlade C.J. Tremblay M.L. Phosphotyrosine-independent binding of SHC to the NPLH sequence of murine protein-tyrosine phosphatase-PEST: Evidence for extended phosphotyrosine binding/phosphotyrosine interaction domain recognition specificity.J Biol Chem. 1996; 271: 8424-8429Crossref PubMed Scopus (78) Google Scholar],[39.Paz K. Voliovitch H. Hadari Y.R. Roberts Jr, Ct Leroith D. Zick Y. Interaction between the insulin receptor and its downstream effectors: Use of individually expressed receptor domains for structure/function analysis.J Biol Chem. 1996; 271: 6998-7003Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Second, yeast two hybrid screens and other studies demonstrated that the PTB domain of FE65 and X11 bind proteins independent of phosphotyrosine[40.Fiore F. Zambrano N. Minopoli G. Donini V. Duilio A. Russo T. The regions of the Fe65 protein homologous to the phosphotyrosine interaction/phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer's amyloid precursor protein.J Biol Chem. 1995; 270: 30853-30856Crossref PubMed Scopus (262) Google Scholar],[41.Borg J.P. Ooi J. Levy E. Margolis B. The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein.Mol Cell Biol. 1996; 16: 6229-6241Crossref PubMed Scopus (421) Google Scholar]. These PTB domains have been shown to bind amyloid precursor protein (APP) in a phosphotyrosine-independent fashion. APP is involved in the pathogenesis of Alzheimer's disease. APP is broken down to the amyloid β protein via a series of intracellular proteases, and this amyloid β is felt to be crucial in the pathogenesis of Alzheimer's disease[42.Selkoe D.J. Alzheimer's disease: Genotypes, phenotypes, and treatments.Science. 1997; 275: 630-631Crossref PubMed Scopus (830) Google Scholar]. APP has a short intracellular domain that includes the sequence motif YENPTY. Our group has shown that this YENPTY motif can bind to the X11 PTB domain without being tyrosine phosphorylated[41.Borg J.P. Ooi J. Levy E. Margolis B. The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein.Mol Cell Biol. 1996; 16: 6229-6241Crossref PubMed Scopus (421) Google Scholar]. A structure of this peptide bound to the X11 PTB domain shows that the X11 PTB domain structure is very similar to the structure of the Shc and IRS PTB domains[43.Zhang Z. Lee C.-H. Mandiyan V. Borg J.-P. Margolis B. Schlessinger J. Kuriyan J. Sequence-specific recognition of the internalization motif of the Alzheimer's amyloid precursor protein by the X11 PTB domain.EMBO J. 1997; 16: 6141-6150Crossref PubMed Scopus (135) Google Scholar]. The YENPTY peptide from APP makes a β turn and binds in a similar fashion as the Shc PTB domain binds to the ψXNPXpY motif. However, in the case of the X11–APP interaction, no phosphotyrosine is required, and phenylalanine residues carboxy terminal to the YENPTY motif also play a role in the interaction Figure 1. Studies have indicated that the interaction of X11 and APP can modulate the breakdown of APP and might play a role in Alzheimer's disease pathogenesis[44.Borg J.P. Yang Y. de Taddeo-Borg M. Margolis B. Turner R.S. The X11alpha protein slows cellular amyloid precursor protein processing and reduces Abeta40 and Abeta42 secretion.J Biol Chem. 1998; 273: 14761-14766Crossref PubMed Scopus (179) Google Scholar]. FE65 has two PTB domains; the carboxy-terminal PTB domain can bind to APP, whereas the amino-terminal PTB domain can bind to the low-density lipoprotein-related (LRP) receptor[45.Trommsdorff M. Borg J. Margolis B. Herz J. Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein.J Biol Chem. 1998; 273: 33556-33565Crossref PubMed Scopus (473) Google Scholar]. The LDL receptor family members such as LRP have multiple β turn motifs in their intracellular region[46.Chen W.J. Goldstein J.L. Brown M.S. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor.J Biol Chem. 1990; 265: 3116-3123Abstract Full Text PDF PubMed Google Scholar] and are natural targets for PTB domain binding. The binding of LRP to FE65 may have important implications for Alzheimer's disease pathogenesis. Apolipoprotein E (apoE) can bind to LRP, and polymorphisms of apoE have important effects on Alzheimer's susceptibility[42.Selkoe D.J. Alzheimer's disease: Genotypes, phenotypes, and treatments.Science. 1997; 275: 630-631Crossref PubMed Scopus (830) Google Scholar]. However, the molecular mechanism that links apoE polymorphisms to Alzheimer's susceptibility is unclear. FE65 potentially provides such a molecular link between apoE polymorphisms and APP breakdown, but further studies on this are necessary. Extensive studies have been performed on the function of the Numb PTB domain. As stated earlier in this article, Numb has an important role in cell fate determination in Drosophila. One system that has been extensively studied is the formation of the peripheral nervous system of Drosophila. The sensory organ precursor cell divides twice to form the four cells that make up the sensory organs of the peripheral nervous system of the fly. When the sensory organ precursor divides, all of Numb localizes to one side of the cell such that only one daughter cell receives Numb[47.Rhyu M.S. January L.Y. January Y.N. Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells.Cell. 1994; 76: 477-491Abstract Full Text PDF PubMed Scopus (614) Google Scholar]. Once localized, Numb can alter the cell fate of the daughter cell. It has been shown that mutagenesis of the Numb PTB domain abrogates its ability to alter cell fate[48.Frise E. Knoblich J.A. Younger-Shepherd S. January L.Y. January Y.N. The Drosophila Numb protein inhibits signaling of the Notch receptor during cell–cell interaction in sensory organ lineage.Proc Natl Acad Sci USA. 1996; 93: 11925-11932Crossref PubMed Scopus (256) Google Scholar],[49.Yaich L. Ooi J. Park M. Borg J.P. Landry C. Bodmer R. Margolis B. Functional analysis of the numb phosphotyrosine binding domain using site directed mutagenesis.J Biol Chem. 1998; 273: 10381-10388Crossref PubMed Scopus (35) Google Scholar]. Mutations of residues in the Numb PTB domain that have been shown to be crucial for phosphotyrosine binding by the Shc PTB domain do not affect Numb function. However, mutation of the residues in the Numb PTB domain that bind residues other than phosphotyrosine blocks Numb function[49.Yaich L. Ooi J. Park M. Borg J.P. Landry C. Bodmer R. Margolis B. Functional analysis of the numb phosphotyrosine binding domain using site directed mutagenesis.J Biol Chem. 1998; 273: 10381-10388Crossref PubMed Scopus (35) Google Scholar]. Several proteins have been found to bind to the Numb PTB domain both in mammalian and Drosophila cells Figure 1, and it appears that these proteins do not need to be tyrosine phosphorylated to bind the Numb PTB domain. One of these proteins identified in Drosophila is called Numb-associated kinase (NAK), a serine threonine kinase without a clear functional role[50.Chien C.T. Wang S. Rothenberg M. January L.Y. January Y.N. Numb-associated kinase interacts with the phosphotyrosine binding domain of Numb and antagonizes the function of Numb in vivo.Mol Cell Biol. 1998; 18: 598-607Crossref PubMed Scopus (64) Google Scholar]. Another Numb-binding partner is called LNX, a protein identified in mammalian cells, which contains several PDZ domains (discussed later in this article) and could function in Numb localization[51.Dho S.E. Jacob S. Wolting C.D. French M.B. Rohrschneider L.R. McGlade C.J. The mammalian numb phosphotyrosine-binding domain: Characterization of binding specificity and identification of a novel PDZ domain-containing numb binding protein, LNX.J Biol Chem. 1998; 273: 9179-9187Crossref PubMed Scopus (95) Google Scholar]. More recently, a protein in Drosophila called partner of Numb (PON) has been shown to bind to the Numb PTB domain independently of phosphotyrosine[52.Lu B. Rothenberg M. January L.Y. January Y.N. Partner of Numb colocalizes with Numb during mitosis and directs Numb asymmetric localization in Drosophila neural and muscle progenitors.Cell. 1998; 95: 225-235Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]. This interaction appears to be very important for Numb localization in certain cells. Most recently, our group has focused extensively on the X11 family of proteins. As indicated in Figure 2, these proteins have one PTB domain as well as two PDZ domains. Our group has identified three forms of X11: X11α, X11β, and X11γ[53.Borg J.-P. Straight S.W. Kaech S.M. de Taddeo-Borg M. Kroon D.E. Karnak D. Turner R.S. Kim S.K. Margolis B. Identification of an evolutionarily conserved heterotrimeric protein complex involved in protein targeting.J Biol Chem. 1998; 273: 31633-31636Crossref PubMed Scopus (166) Google Scholar]. These proteins have also been referred to as Mint1, Mint2, and Mint3[54.Okamoto M. Sudhof T.C. Mints, Munc18-interacting proteins in synaptic vesicle exocytosis.J Biol Chem. 1997; 272: 31459-31464Crossref PubMed Scopus (268) Google Scholar],[55.Butz S. Okamoto M. Sudhof T.C. A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain.Cell. 1998; 94: 773-782Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar]. X11α and X11β appear to be expressed primarily in the central nervous system. As previously discussed, the X11α PTB domain can interact with APP. We have shown that overexpression of X11 in cells reduces the processing of APP to amyloid β protein[44.Borg J.P. Yang Y. de Taddeo-Borg M. Margolis B. Turner R.S. The X11alpha protein slows cellular amyloid precursor protein processing and reduces Abeta40 and Abeta42 secr
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