| Structural highlights
Function
FER_HUMAN Tyrosine-protein kinase that acts downstream of cell surface receptors for growth factors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, lamellipodia formation, cell adhesion, cell migration and chemotaxis. Acts downstream of EGFR, KIT, PDGFRA and PDGFRB. Acts downstream of EGFR to promote activation of NF-kappa-B and cell proliferation. May play a role in the regulation of the mitotic cell cycle. Plays a role in the insulin receptor signaling pathway and in activation of phosphatidylinositol 3-kinase. Acts downstream of the activated FCER1 receptor and plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Plays a role in the regulation of mast cell degranulation. Plays a role in leukocyte recruitment and diapedesis in response to bacterial lipopolysaccharide (LPS). Plays a role in synapse organization, trafficking of synaptic vesicles, the generation of excitatory postsynaptic currents and neuron-neuron synaptic transmission. Plays a role in neuronal cell death after brain damage. Phosphorylates CTTN, CTNND1, PTK2/FAK1, GAB1, PECAM1 and PTPN11. May phosphorylate JUP and PTPN1. Can phosphorylate STAT3, but the biological relevance of this depends on cell type and stimulus.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
Fes and Fes-related (Fer) protein tyrosine kinases (PTKs) comprise a subfamily of nonreceptor tyrosine kinases characterized by a unique multidomain structure composed of an N-terminal Fer/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain, a central Src homology 2 (SH2) domain, and a C-terminal PTK domain. Fer is ubiquitously expressed, and upregulation of Fer has been implicated in various human cancers. The PTK activity of Fes has been shown to be positively regulated by the binding of phosphotyrosine-containing ligands to the SH2 domain. Here, the X-ray crystal structure of human Fer SH2 domain bound to a phosphopeptide that has D-E-pY-E-N-V-D sequence is reported at 1.37 a resolution. The asymmetric unit (ASU) contains six Fer-phosphopeptide complexes, and the structure reveals three distinct binding modes for the same phosphopeptide. At four out of the six binding sites in the ASU, the phosphopeptide binds to Fer SH2 domain in a type I beta-turn conformation, and this could be the optimal binding mode of this phosphopeptide. At the other two binding sites in the ASU, it appears that spatial proximity of neighboring SH2 domains in the crystal induces alternative modes of binding of this phosphopeptide.
High-resolution structural analysis shows how different crystallographic environments can induce alternative modes of binding of a phosphotyrosine peptide to the SH2 domain of Fer tyrosine kinase.,Matsuura Y Protein Sci. 2019 Nov;28(11):2011-2019. doi: 10.1002/pro.3713. Epub 2019 Aug 31. PMID:31441171[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Makovski A, Yaffe E, Shpungin S, Nir U. Intronic promoter drives the BORIS-regulated expression of FerT in colon carcinoma cells. J Biol Chem. 2012 Feb 24;287(9):6100-12. doi: 10.1074/jbc.M111.327106. Epub 2012 , Jan 5. PMID:22223638 doi:http://dx.doi.org/10.1074/jbc.M111.327106
- ↑ Kim L, Wong TW. The cytoplasmic tyrosine kinase FER is associated with the catenin-like substrate pp120 and is activated by growth factors. Mol Cell Biol. 1995 Aug;15(8):4553-61. PMID:7623846
- ↑ Kim L, Wong TW. Growth factor-dependent phosphorylation of the actin-binding protein cortactin is mediated by the cytoplasmic tyrosine kinase FER. J Biol Chem. 1998 Sep 4;273(36):23542-8. PMID:9722593
- ↑ Kogata N, Masuda M, Kamioka Y, Yamagishi A, Endo A, Okada M, Mochizuki N. Identification of Fer tyrosine kinase localized on microtubules as a platelet endothelial cell adhesion molecule-1 phosphorylating kinase in vascular endothelial cells. Mol Biol Cell. 2003 Sep;14(9):3553-64. Epub 2003 Jun 13. PMID:12972546 doi:http://dx.doi.org/10.1091/mbc.E03-02-0080
- ↑ Miravet S, Piedra J, Castano J, Raurell I, Franci C, Dunach M, Garcia de Herreros A. Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcription. Mol Cell Biol. 2003 Oct;23(20):7391-402. PMID:14517306
- ↑ Oh MA, Choi S, Lee MJ, Choi MC, Lee SA, Ko W, Cance WG, Oh ES, Buday L, Kim SH, Lee JW. Specific tyrosine phosphorylation of focal adhesion kinase mediated by Fer tyrosine kinase in suspended hepatocytes. Biochim Biophys Acta. 2009 May;1793(5):781-91. doi: 10.1016/j.bbamcr.2009.01.015., Epub 2009 Feb 5. PMID:19339212 doi:http://dx.doi.org/10.1016/j.bbamcr.2009.01.015
- ↑ Zoubeidi A, Rocha J, Zouanat FZ, Hamel L, Scarlata E, Aprikian AG, Chevalier S. The Fer tyrosine kinase cooperates with interleukin-6 to activate signal transducer and activator of transcription 3 and promote human prostate cancer cell growth. Mol Cancer Res. 2009 Jan;7(1):142-55. doi: 10.1158/1541-7786.MCR-08-0117. PMID:19147545 doi:http://dx.doi.org/10.1158/1541-7786.MCR-08-0117
- ↑ Itoh T, Hasegawa J, Tsujita K, Kanaho Y, Takenawa T. The tyrosine kinase Fer is a downstream target of the PLD-PA pathway that regulates cell migration. Sci Signal. 2009 Sep 8;2(87):ra52. doi: 10.1126/scisignal.2000393. PMID:19738202 doi:http://dx.doi.org/10.1126/scisignal.2000393
- ↑ Voisset E, Lopez S, Chaix A, Georges C, Hanssens K, Prebet T, Dubreuil P, De Sepulveda P. FES kinases are required for oncogenic FLT3 signaling. Leukemia. 2010 Apr;24(4):721-8. doi: 10.1038/leu.2009.301. Epub 2010 Jan 28. PMID:20111072 doi:10.1038/leu.2009.301
- ↑ Guo C, Stark GR. FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-kappaB. Proc Natl Acad Sci U S A. 2011 May 10;108(19):7968-73. doi:, 10.1073/pnas.1105369108. Epub 2011 Apr 25. PMID:21518868 doi:http://dx.doi.org/10.1073/pnas.1105369108
- ↑ Matsuura Y. High-resolution structural analysis shows how different crystallographic environments can induce alternative modes of binding of a phosphotyrosine peptide to the SH2 domain of Fer tyrosine kinase. Protein Sci. 2019 Nov;28(11):2011-2019. doi: 10.1002/pro.3713. Epub 2019 Aug 31. PMID:31441171 doi:http://dx.doi.org/10.1002/pro.3713
|
