PMID- 25624497 OWN - NLM STAT- MEDLINE DCOM- 20150508 LR - 20220129 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 112 IP - 6 DP - 2015 Feb 10 TI - PTPsigma functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission. PG - 1874-9 LID - 10.1073/pnas.1410138112 [doi] AB - Leukocyte common antigen-related receptor protein tyrosine phosphatases--comprising LAR, PTPdelta, and PTPsigma--are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPsigma. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPsigma. PTPsigma bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPsigma, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPsigma KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPsigma, but not by a HS-binding-defective PTPsigma mutant. Our results collectively suggest that presynaptic PTPsigma, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function. FAU - Ko, Ji Seung AU - Ko JS AD - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; FAU - Pramanik, Gopal AU - Pramanik G AD - Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; National Institute for Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan; FAU - Um, Ji Won AU - Um JW AD - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; FAU - Shim, Ji Seon AU - Shim JS AD - Department of Physiology, Kyung Hee University School of Medicine, Seoul 130-701, Korea; FAU - Lee, Dongmin AU - Lee D AD - Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul 136-705, Korea; FAU - Kim, Kee Hun AU - Kim KH AD - Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; FAU - Chung, Gug-Young AU - Chung GY AD - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; FAU - Condomitti, Giuseppe AU - Condomitti G AD - VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium; FAU - Kim, Ho Min AU - Kim HM AD - Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; FAU - Kim, Hyun AU - Kim H AD - Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul 136-705, Korea; FAU - de Wit, Joris AU - de Wit J AD - VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium; FAU - Park, Kang-Sik AU - Park KS AD - Department of Physiology, Kyung Hee University School of Medicine, Seoul 130-701, Korea; FAU - Tabuchi, Katsuhiko AU - Tabuchi K AD - Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; National Institute for Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan; and. FAU - Ko, Jaewon AU - Ko J AD - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; Department of Psychiatry, Yonsei University College of Medicine, Seoul 120-751, Korea jaewonko@yonsei.ac.kr. LA - eng GR - 311083/ERC_/European Research Council/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150126 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Glypicans) RN - 0 (Leucine-Rich Repeat Proteins) RN - 0 (Multiprotein Complexes) RN - 0 (Oligonucleotides) RN - 0 (Proteins) RN - 9050-30-0 (Heparitin Sulfate) RN - EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 2) SB - IM MH - Analysis of Variance MH - Animals MH - Blotting, Western MH - Brain/*metabolism MH - Chromatography, Affinity MH - Chromatography, High Pressure Liquid MH - Gene Knockdown Techniques MH - Genetic Vectors/genetics MH - Glypicans/*metabolism MH - Heparitin Sulfate/metabolism MH - Immunohistochemistry MH - Immunoprecipitation MH - In Situ Hybridization MH - Leucine-Rich Repeat Proteins MH - Mass Spectrometry MH - Multiprotein Complexes/*metabolism MH - Oligonucleotides/genetics MH - Presynaptic Terminals/physiology MH - Proteins/*metabolism MH - Rats MH - Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics/*metabolism MH - Synaptic Transmission/*physiology PMC - PMC4330736 OTO - NOTNLM OT - LRRTM4 OT - PTPsigma OT - glypican OT - heparan sulfate OT - synaptic cell adhesion COIS- The authors declare no conflict of interest. EDAT- 2015/01/28 06:00 MHDA- 2015/05/09 06:00 PMCR- 2015/08/10 CRDT- 2015/01/28 06:00 PHST- 2015/01/28 06:00 [entrez] PHST- 2015/01/28 06:00 [pubmed] PHST- 2015/05/09 06:00 [medline] PHST- 2015/08/10 00:00 [pmc-release] AID - 1410138112 [pii] AID - 201410138 [pii] AID - 10.1073/pnas.1410138112 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1874-9. doi: 10.1073/pnas.1410138112. Epub 2015 Jan 26.