Note | PTK7 has a classical RTK structure with an extracellular region, a single transmembrane region and an intracellular tyrosine kinase domain. |
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| A. Structure and organization of PTK7 gene. Each box represents an exon. B. Structure and features of PTK7 protein. Structure and mapping of each immunoglobulin-like loop domains are indicated in the figure. The main features of the protein (i.e cleavage site and non-classical residues in the catalytic domain) are mentioned in the figure. Ig: immunoglobulin loops domain.TM: transmembrane domain. JM: juxtamembrane domain. |
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Description | The human and mouse PTK7 proteins comprise 1070 and 1062 amino acids, respectively, and share 92.6% identity. The extracellular region is composed by seven immunoglobulin-like domains. Although the kinase domain is catalytically inactive, it is highly evolutionarily conserved during evolution. Three major non-classical sequences have been described: the GXGXXG ATP binding motif is changed in GXSXXG. The HDRL motif required for the catalytic proton transfer is changed in a HKDL motif, and the aspartate residue of the DFG motif usually coordinating Mg2+-ATP binding is changed to an uncharged alanine residue (ALG motif) (Jung et al., 2004; Boudeau et al., 2006). No convincing experimental data support yet a catalytic function of the PTK7 tyrosine kinase domain. |
Expression | PTK7 is ubiquitously expressed at low level in epithelial, endothelial and hematopoietic tissues. PTK7 is highly expressed in tumoral tissues: colon cancer (Mossie et al., 1995), melanoma (Easty et al., 1997), breast cancer (Speers et al., 2009), acute myeloid leukemia, acute lymphoid leukemia (Müller-Tidow et al., 2004; Prébet et al., 2010). |
Localisation | PTK7 is localized at the plasma membrane and has its extracellular domain exposed at the cell surface. It is described that PTK7 is processed by MT1-MPP, a metalloproteinase, that releases a soluble form of PTK7. From in vivo and in vitro studies, it appears that a fine-tuned balance between full length PTK7 and soluble PTK7 is required for normal embryonic development and directional cell migration (Golubkov et al., 2010; Golubkov et al., 2011). |
Function | The loss of PTK7 protein in mouse leads to a severe and lethal phenotype of neural tube defect closure (craniorachischisis) and abdomen defect closure. Also, PTK7 is implicated in planar cell polarity and in the convergent extension embryonic process (Lu et al., 2004; Yen et al., 2009). Despite the lack of tyrosine kinase activity, PTK7 is involved in epithelial and hematopoietic cell migration. PTK7 is able to interact with VEGFR1 and is implicated into angiogenesis (Shin et al., 2008; Lee et al., 2011). In term of signaling, PTK7 is able to bind to β-catenin and Dsh proteins (Shnitsar and Borchers, 2008). The formation of a tripartite complex Dsh-Rack1-Fz7 places PTK7 as an actor of non-canonical Wnt pathway (Wehner et al., 2011). Interaction with β-catenin suggests that PTK7 is also involved in canonical Wnt pathway (Puppo et al., 2011). However, the role of PTK7 as activator or inhibitor of Wnt canonical signaling is still controversial (Peradziryi et al., 2011). In Drosophila, PTK7 (also called OTK) forms a protein complex with members of the Plexin family proteins. Also, OTK is apparently also involved in the Plexin-Semaphorin pathway (Wagner et al., 2010). |
Homology | The extracellular part show similarities with adhesion molecules of the immunoglobulin superfamily due to the presence of immunoglobulin loops domains. Phylogenetic study showed that among the RTKs of the immunoglobulin superfamily, ptk7 and musk genes have derived very early during evolution and have created an independent branch probably endowed with particular functions. Indeed, Musk shows the highest identity sequence with PTK7 (42%) when the extracellular domains are compared (Grassot et al., 2006). |
Assignment of PTK7 encoding a receptor protein tyrosine kinase-like molecule to human chromosome 6p21.1-->p12.2 by fluorescence in situ hybridization. |
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Potential relation of aberrant proteolysis of human protein tyrosine kinase 7 (PTK7) chuzhoi by membrane type 1 matrix metalloproteinase (MT1-MMP) to congenital defects. |
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J Biol Chem. 2011 Jun 10;286(23):20970-6. Epub 2011 Apr 25. |
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Origin and molecular evolution of receptor tyrosine kinases with immunoglobulin-like domains. |
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Organization of the human PTK7 gene encoding a receptor protein tyrosine kinase-like molecule and alternative splicing of its mRNA. |
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Cloning and characterization of the full-length mouse Ptk7 cDNA encoding a defective receptor protein tyrosine kinase. |
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Blood. 2011 May 26;117(21):5762-71. Epub 2011 Apr 1. |
PMID 21460247 |
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PTK7: a cell polarity receptor with multiple facets. |
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PMID 21415598 |
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PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. |
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Nature. 2004 Jul 1;430(6995):93-8. |
PMID 15229603 |
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Noncanonical Wnt signaling and neural polarity. |
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PMID 16776590 |
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Colon carcinoma kinase-4 defines a new subclass of the receptor tyrosine kinase family. |
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PMID 7478540 |
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High-throughput analysis of genome-wide receptor tyrosine kinase expression in human cancers identifies potential novel drug targets. |
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Clin Cancer Res. 2004 Feb 15;10(4):1241-9. |
PMID 14977821 |
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Characterization of the human full-length PTK7 cDNA encoding a receptor protein tyrosine kinase-like molecule closely related to chick KLG. |
Park SK, Lee HS, Lee ST. |
J Biochem. 1996 Feb;119(2):235-9. |
PMID 8882711 |
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The many roles of PTK7: A versatile regulator of cell-cell communication. |
Peradziryi H, Tolwinski NS, Borchers A. |
Arch Biochem Biophys. 2012 Aug 1;524(1):71-6. Epub 2012 Jan 3. |
PMID 22230326 |
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The cell polarity PTK7 receptor acts as a modulator of the chemotherapeutic response in acute myeloid leukemia and impairs clinical outcome. |
Prebet T, Lhoumeau AC, Arnoulet C, Aulas A, Marchetto S, Audebert S, Puppo F, Chabannon C, Sainty D, Santoni MJ, Sebbagh M, Summerour V, Huon Y, Shin WS, Lee ST, Esterni B, Vey N, Borg JP. |
Blood. 2010 Sep 30;116(13):2315-23. Epub 2010 Jun 17. |
PMID 20558616 |
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Protein tyrosine kinase 7 has a conserved role in Wnt/?-catenin canonical signalling. |
Puppo F, Thome V, Lhoumeau AC, Cibois M, Gangar A, Lembo F, Belotti E, Marchetto S, Lecine P, Prebet T, Sebbagh M, Shin WS, Lee ST, Kodjabachian L, Borg JP. |
EMBO Rep. 2011 Jan;12(1):43-9. Epub 2010 Dec 3. |
PMID 21132015 |
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Cdx mediates neural tube closure through transcriptional regulation of the planar cell polarity gene Ptk7. |
Savory JG, Mansfield M, Rijli FM, Lohnes D. |
Development. 2011 Apr;138(7):1361-70. Epub 2011 Feb 24. |
PMID 21350009 |
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Soluble PTK7 inhibits tube formation, migration, and invasion of endothelial cells and angiogenesis. |
Shin WS, Maeng YS, Jung JW, Min JK, Kwon YG, Lee ST. |
Biochem Biophys Res Commun. 2008 Jul 11;371(4):793-8. Epub 2008 May 8. |
PMID 18471990 |
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PTK7 recruits dsh to regulate neural crest migration. |
Shnitsar I, Borchers A. |
Development. 2008 Dec;135(24):4015-24. Epub 2008 Nov 12. |
PMID 19004858 |
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Identification of novel kinase targets for the treatment of estrogen receptor-negative breast cancer. |
Speers C, Tsimelzon A, Sexton K, Herrick AM, Gutierrez C, Culhane A, Quackenbush J, Hilsenbeck S, Chang J, Brown P. |
Clin Cancer Res. 2009 Oct 15;15(20):6327-40. Epub 2009 Oct 6. |
PMID 19808870 |
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PlexinA1 interacts with PTK7 and is required for neural crest migration. |
Wagner G, Peradziryi H, Wehner P, Borchers A. |
Biochem Biophys Res Commun. 2010 Nov 12;402(2):402-7. Epub 2010 Oct 12. |
PMID 20946874 |
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RACK1 is a novel interaction partner of PTK7 that is required for neural tube closure. |
Wehner P, Shnitsar I, Urlaub H, Borchers A. |
Development. 2011 Apr;138(7):1321-7. Epub 2011 Feb 24. |
PMID 21350015 |
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PTK7 is essential for polarized cell motility and convergent extension during mouse gastrulation. |
Yen WW, Williams M, Periasamy A, Conaway M, Burdsal C, Keller R, Lu X, Sutherland A. |
Development. 2009 Jun;136(12):2039-48. Epub 2009 May 13. |
PMID 19439496 |
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