Pleiotrophin Explained

Pleiotrophin (PTN) also known as heparin-binding brain mitogen (HBBM) or heparin-binding growth factor 8 (HBGF-8) or neurite growth-promoting factor 1 (NEGF1) or heparin affinity regulatory peptide (HARP) or heparin binding growth associated molecule (HB-GAM) is a protein that in humans is encoded by the PTN gene.^[1] Pleiotrophin is an 18-kDa growth factor that has a high affinity for heparin. It is structurally related to midkine and retinoic acid induced heparin-binding protein.

Function

Pleiotrophin was initially recognized as a neurite outgrowth-promoting factor present in rat brain around birth^[2] and as a mitogen toward fibroblasts isolated from bovine uterus tissue.^[3] Together with midkine these growth-factors constitute a family of (developmentally regulated) secreted heparin-binding proteins^[4] now known as the neurite growth-promoting factor (NEGF) family. During embryonic and early postnatal development, pleiotrophin is expressed in the central and peripheral nervous system and also in several non-neural tissues, notably lung, kidney, gut and bone.^[5] Pleiotrophin is also expressed by several tumor cells and is thought to be involved in tumor angiogenesis.^[6] In the adult central nervous system, pleiotrophin is expressed in an activity-dependent manner in the hippocampus^{[7] [8]} where it can suppress long term potentiation induction.^[9] Pleiotrophin expression is low in other areas of the adult brain, but it can be induced by ischemic insults.^{[10] [11]} or targeted neuronal damaged in the entorhinal cortex or in the substantia nigra pars compacta.

Clinical significance

Pleiotrophin binds to cell-surface nucleolin as a low affinity receptor. This binding can inhibit HIV infection.^[12]

Further reading

• Milner PG, Shah D, Veile R, etal . Cloning, nucleotide sequence, and chromosome localization of the human pleiotrophin gene. . Biochemistry . 31 . 48 . 12023–8 . 1993 . 1457401 . 10.1021/bi00163a009 .
• Li YS, Hoffman RM, Le Beau MM, etal . Characterization of the human pleiotrophin gene. Promoter region and chromosomal localization. . J. Biol. Chem. . 267 . 36 . 26011–6 . 1993 . 10.1016/S0021-9258(18)35709-0 . 1464612 . free .
• Tezuka K, Takeshita S, Hakeda Y, etal . Isolation of mouse and human cDNA clones encoding a protein expressed specifically in osteoblasts and brain tissues. . Biochem. Biophys. Res. Commun. . 173 . 1 . 246–51 . 1991 . 1701634 . 10.1016/S0006-291X(05)81048-4 .
• Wellstein A, Fang WJ, Khatri A, etal . A heparin-binding growth factor secreted from breast cancer cells homologous to a developmentally regulated cytokine. . J. Biol. Chem. . 267 . 4 . 2582–7 . 1992 . 10.1016/S0021-9258(18)45920-0 . 1733956 . free .
• Kretschmer PJ, Fairhurst JL, Decker MM, etal . Cloning, characterization and developmental regulation of two members of a novel human gene family of neurite outgrowth-promoting proteins. . Growth Factors . 5 . 2 . 99–114 . 1992 . 1768439 . 10.3109/08977199109000275 .
• Li YS, Milner PG, Chauhan AK, etal . Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity. . Science . 250 . 4988 . 1690–4 . 1991 . 2270483 . 10.1126/science.2270483 . 1990Sci...250.1690L .
• Huber D, Gautschi-Sova P, Böhlen P . Amino-terminal sequences of a novel heparin-binding protein from human, bovine, rat, and chick brain: high interspecies homology. . Neurochem. Res. . 15 . 4 . 435–9 . 1990 . 2388713 . 10.1007/BF00969930 . 24896178 .
• Asundi VK, Carey DJ . Self-association of N-syndecan (syndecan-3) core protein is mediated by a novel structural motif in the transmembrane domain and ectodomain flanking region. . J. Biol. Chem. . 270 . 44 . 26404–10 . 1995 . 7592855 . 10.1074/jbc.270.44.26404 . free .
• Raulo E, Chernousov MA, Carey DJ, etal . Isolation of a neuronal cell surface receptor of heparin binding growth-associated molecule (HB-GAM). Identification as N-syndecan (syndecan-3). . J. Biol. Chem. . 269 . 17 . 12999–3004 . 1994 . 10.1016/S0021-9258(18)99975-8 . 8175719 . free .
• Fabri L, Maruta H, Muramatsu H, etal . Structural characterisation of native and recombinant forms of the neurotrophic cytokine MK. . J. Chromatogr. . 646 . 1 . 213–25 . 1993 . 8408430 . 10.1016/S0021-9673(99)87023-X .
• Kretschmer PJ, Fairhurst JL, Hulmes JD, etal . Genomic organization of the human HBNF gene and characterization of an HBNF variant protein as a splice mutant. . Biochem. Biophys. Res. Commun. . 192 . 2 . 420–9 . 1993 . 8484754 . 10.1006/bbrc.1993.1432 .
• Hulmes JD, Seddon AP, Decker MM, Böhlen P . Comparison of the disulfide bond arrangements of human recombinant and bovine brain heparin binding neurite-promoting factors. . Biochem. Biophys. Res. Commun. . 192 . 2 . 738–46 . 1993 . 8484780 . 10.1006/bbrc.1993.1476 .
• Kinnunen T, Raulo E, Nolo R, etal . Neurite outgrowth in brain neurons induced by heparin-binding growth-associated molecule (HB-GAM) depends on the specific interaction of HB-GAM with heparan sulfate at the cell surface. . J. Biol. Chem. . 271 . 4 . 2243–8 . 1996 . 8567685 . 10.1074/jbc.271.4.2243 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery. . Genome Res. . 6 . 9 . 791–806 . 1997 . 8889548 . 10.1101/gr.6.9.791 . free .
• Masuda H, Tsujimura A, Yoshioka M, etal . Bone mass loss due to estrogen deficiency is compensated in transgenic mice overexpressing human osteoblast stimulating factor-1. . Biochem. Biophys. Res. Commun. . 238 . 2 . 528–33 . 1997 . 9299545 . 10.1006/bbrc.1997.7188 .
• Milev P, Chiba A, Häring M, etal . High affinity binding and overlapping localization of neurocan and phosphacan/protein-tyrosine phosphatase-zeta/beta with tenascin-R, amphoterin, and the heparin-binding growth-associated molecule. . J. Biol. Chem. . 273 . 12 . 6998–7005 . 1998 . 9507007 . 10.1074/jbc.273.12.6998 . free .
• Fages C, Kaksonen M, Kinnunen T, etal . Regulation of mRNA localization by transmembrane signalling: local interaction of HB-GAM (heparin-binding growth-associated molecule) with the cell surface localizes beta-actin mRNA. . J. Cell Sci. . 111 . 20. 3073–80 . 1998 . 10.1242/jcs.111.20.3073 . 9739080 . free .
• Zhang N, Zhong R, Deuel TF . Domain structure of pleiotrophin required for transformation. . J. Biol. Chem. . 274 . 19 . 12959–62 . 1999 . 10224041 . 10.1074/jbc.274.19.12959 . free .
• Bernard-Pierrot I, Héroult M, Lemaître G, etal . Glycosaminoglycans promote HARP/PTN dimerization. . Biochem. Biophys. Res. Commun. . 266 . 2 . 437–42 . 2000 . 10600521 . 10.1006/bbrc.1999.1835 .
• Meng K, Rodriguez-Peña A, Dimitrov T, etal . Pleiotrophin signals increased tyrosine phosphorylation of beta beta-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase beta/zeta. . Proc. Natl. Acad. Sci. U.S.A. . 97 . 6 . 2603–8 . 2000 . 10706604 . 10.1073/pnas.020487997 . 15975 . free .
• Murasugi A, Kido I, Kumai H, Asami Y . Efficient production of recombinant human pleio-trophin in yeast, Pichia pastoris. . Biosci. Biotechnol. Biochem. . 67 . 10 . 2288–90 . 2003 . 14586125 . 10.1271/bbb.67.2288 . 23168994 .

Notes and References

1. Web site: Entrez Gene: PTN pleiotrophin (heparin binding growth factor 8, neurite growth-promoting factor 1).
2. Rauvala H, Pihlaskari R . Isolation and some characteristics of an adhesive factor of brain that enhances neurite outgrowth in central neurons . J. Biol. Chem. . 262 . 34 . 16625–35 . 1987 . 10.1016/S0021-9258(18)49302-7 . 3680268 . free .
3. Li YS, Milner PG, Chauhan AK, Watson MA, Hoffman RM, Kodner CM, Milbrandt J, Deuel TF . Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity . Science . 250 . 4988 . 1690–4 . 1990 . 2270483 . 10.1126/science.2270483 . 1990Sci...250.1690L .
4. Laaroubi K, Vacherot F, Delbé J, Caruelle D, Barritault D, Courty J . Biochemical and mitogenic properties of the heparin-binding growth factor HARP . Prog. Growth Factor Res. . 6 . 1 . 25–34 . 1995 . 8714367 . 10.1016/0955-2235(95)00002-X .
5. Vanderwinden JM, Mailleux P, Schiffmann SN, Vanderhaeghen JJ . Cellular distribution of the new growth factor pleiotrophin (HB-GAM) mRNA in developing and adult rat tissues . Anat. Embryol. . 186 . 4 . 387–406 . 1992 . 1416088 . 10.1007/BF00185989 . 23579980 .
6. Kadomatsu K, Muramatsu T . Midkine and pleiotrophin in neural development and cancer . Cancer Lett. . 204 . 2 . 127–43 . 2004 . 15013213 . 10.1016/S0304-3835(03)00450-6 .
7. Wanaka A, Carroll SL, Milbrandt J . Developmentally regulated expression of pleiotrophin, a novel heparin binding growth factor, in the nervous system of the rat . Brain Res. Dev. Brain Res. . 72 . 1 . 133–44 . 1993 . 8453763 . 10.1016/0165-3806(93)90166-8 .
8. Lauri SE, Taira T, Kaila K, Rauvala H . Activity-induced enhancement of HB-GAM expression in rat hippocampal slices . NeuroReport . 7 . 10 . 1670–4 . 1996 . 8904779 . 10.1097/00001756-199607080-00029 .
9. Pavlov I, Võikar V, Kaksonen M, Lauri SE, Hienola A, Taira T, Rauvala H . Role of heparin-binding growth-associated molecule (HB-GAM) in hippocampal LTP and spatial learning revealed by studies on overexpressing and knockout mice . Mol. Cell. Neurosci. . 20 . 2 . 330–42 . 2002 . 12093164 . 10.1006/mcne.2002.1104 . 24655036 .
10. Takeda A, Onodera H, Sugimoto A, Itoyama Y, Kogure K, Rauvala H, Shibahara S . Induction of heparin-binding growth-associated molecule expression in reactive astrocytes following hippocampal neuronal injury . Neuroscience . 68 . 1 . 57–64 . 1995 . 7477935 . 10.1016/0306-4522(95)00110-5 . 32945854 .
11. Yeh HJ, He YY, Xu J, Hsu CY, Deuel TF . Upregulation of pleiotrophin gene expression in developing microvasculature, macrophages, and astrocytes after acute ischemic brain injury . J. Neurosci. . 18 . 10 . 3699–707 . 1998 . 9570800 . 10.1523/JNEUROSCI.18-10-03699.1998. 6793139 .
12. Said EA, Courty J, Svab J, Delbé J, Krust B, Hovanessian AG . Pleiotrophin inhibits HIV infection by binding the cell surface-expressed nucleolin . FEBS J. . 272 . 18 . 4646–59 . September 2005 . 16156786 . 10.1111/j.1742-4658.2005.04870.x . 21153881 . free .