| Structural highlights
Function
[FYN_HUMAN] Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]
Publication Abstract from PubMed
Interactions of proline-rich motifs with SH3 domains are present in signal transduction and other important cell processes. Analysis of structural and thermodynamic data suggest a relevant role of water molecules in these protein-protein interactions. To determine whether or not the SH3 domain of the Fyn tyrosine kinase shows the same behaviour, the crystal structures of its complexes with two high-affinity synthetic peptides, VSL12 and APP12, which are class I and II peptides, respectively, have been solved. In the class I complexes two water molecules were found at the binding interface that were not present in the class II complexes. The structures suggest a role of these water molecules in facilitating conformational changes in the SH3 domain to allow the binding of the class I or II peptides. In the third binding pocket these changes modify the cation-pi and salt-bridge interactions that determine the affinity of the binding. Comparison of the water molecules involved in the binding of the peptides with previous reported hydration spots suggests a different pattern for the SH3 domains of the Src tyrosine kinase family.
The role of water molecules in the binding of class I and II peptides to the SH3 domain of the Fyn tyrosine kinase.,Camara-Artigas A, Ortiz-Salmeron E, Andujar-Sanchez M, Bacarizo J, Martin-Garcia JM Acta Crystallogr F Struct Biol Commun. 2016 Sep;72(Pt 9):707-12. doi:, 10.1107/S2053230X16012310. Epub 2016 Aug 26. PMID:27599862[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Rigley K, Slocombe P, Proudfoot K, Wahid S, Mandair K, Bebbington C. Human p59fyn(T) regulates OKT3-induced calcium influx by a mechanism distinct from PIP2 hydrolysis in Jurkat T cells. J Immunol. 1995 Feb 1;154(3):1136-45. PMID:7822789
- ↑ Raab M, Cai YC, Bunnell SC, Heyeck SD, Berg LJ, Rudd CE. p56Lck and p59Fyn regulate CD28 binding to phosphatidylinositol 3-kinase, growth factor receptor-bound protein GRB-2, and T cell-specific protein-tyrosine kinase ITK: implications for T-cell costimulation. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8891-5. PMID:7568038
- ↑ Huang J, Tilly D, Altman A, Sugie K, Grey HM. T-cell receptor antagonists induce Vav phosphorylation by selective activation of Fyn kinase. Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10923-9. PMID:11005864
- ↑ Nakamura T, Yamashita H, Takahashi T, Nakamura S. Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125. Biochem Biophys Res Commun. 2001 Feb 2;280(4):1085-92. PMID:11162638 doi:10.1006/bbrc.2000.4253
- ↑ Wolf RM, Wilkes JJ, Chao MV, Resh MD. Tyrosine phosphorylation of p190 RhoGAP by Fyn regulates oligodendrocyte differentiation. J Neurobiol. 2001 Oct;49(1):62-78. PMID:11536198
- ↑ Taniguchi S, Liu H, Nakazawa T, Yokoyama K, Tezuka T, Yamamoto T. p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn. Biochem Biophys Res Commun. 2003 Jun 20;306(1):151-5. PMID:12788081
- ↑ Piedra J, Miravet S, Castano J, Palmer HG, Heisterkamp N, Garcia de Herreros A, Dunach M. p120 Catenin-associated Fer and Fyn tyrosine kinases regulate beta-catenin Tyr-142 phosphorylation and beta-catenin-alpha-catenin Interaction. Mol Cell Biol. 2003 Apr;23(7):2287-97. PMID:12640114
- ↑ Hisatsune C, Kuroda Y, Nakamura K, Inoue T, Nakamura T, Michikawa T, Mizutani A, Mikoshiba K. Regulation of TRPC6 channel activity by tyrosine phosphorylation. J Biol Chem. 2004 Apr 30;279(18):18887-94. Epub 2004 Feb 3. PMID:14761972 doi:10.1074/jbc.M311274200
- ↑ Meriane M, Tcherkezian J, Webber CA, Danek EI, Triki I, McFarlane S, Bloch-Gallego E, Lamarche-Vane N. Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance. J Cell Biol. 2004 Nov 22;167(4):687-98. PMID:15557120 doi:jcb.200405053
- ↑ Badour K, Zhang J, Shi F, Leng Y, Collins M, Siminovitch KA. Fyn and PTP-PEST-mediated regulation of Wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation. J Exp Med. 2004 Jan 5;199(1):99-112. PMID:14707117 doi:10.1084/jem.20030976
- ↑ Zamora-Leon SP, Bresnick A, Backer JM, Shafit-Zagardo B. Fyn phosphorylates human MAP-2c on tyrosine 67. J Biol Chem. 2005 Jan 21;280(3):1962-70. Epub 2004 Nov 9. PMID:15536091 doi:10.1074/jbc.M411380200
- ↑ Yang C, Zhou W, Jeon MS, Demydenko D, Harada Y, Zhou H, Liu YC. Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol Cell. 2006 Jan 6;21(1):135-41. PMID:16387660 doi:10.1016/j.molcel.2005.11.014
- ↑ Tang X, Feng Y, Ye K. Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival. Cell Death Differ. 2007 Feb;14(2):368-77. Epub 2006 Jul 14. PMID:16841086 doi:10.1038/sj.cdd.4402011
- ↑ Castano J, Solanas G, Casagolda D, Raurell I, Villagrasa P, Bustelo XR, Garcia de Herreros A, Dunach M. Specific phosphorylation of p120-catenin regulatory domain differently modulates its binding to RhoA. Mol Cell Biol. 2007 Mar;27(5):1745-57. Epub 2006 Dec 28. PMID:17194753 doi:10.1128/MCB.01974-06
- ↑ Solheim SA, Torgersen KM, Tasken K, Berge T. Regulation of FynT function by dual domain docking on PAG/Cbp. J Biol Chem. 2008 Feb 1;283(5):2773-83. Epub 2007 Dec 4. PMID:18056706 doi:10.1074/jbc.M705215200
- ↑ Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T, Hattori S. Neph1, a component of the kidney slit diaphragm, is tyrosine-phosphorylated by the Src family tyrosine kinase and modulates intracellular signaling by binding to Grb2. J Biol Chem. 2008 Apr 4;283(14):9177-86. doi: 10.1074/jbc.M707247200. Epub 2008, Feb 7. PMID:18258597 doi:10.1074/jbc.M707247200
- ↑ Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T, Ohsawa I, Ohta S, Hattori S. Phosphorylation of Nephrin Triggers Ca2+ Signaling by Recruitment and Activation of Phospholipase C-{gamma}1. J Biol Chem. 2009 Mar 27;284(13):8951-62. doi: 10.1074/jbc.M806851200. Epub 2009 , Jan 29. PMID:19179337 doi:10.1074/jbc.M806851200
- ↑ Uchida Y, Ohshima T, Yamashita N, Ogawara M, Sasaki Y, Nakamura F, Goshima Y. Semaphorin3A signaling mediated by Fyn-dependent tyrosine phosphorylation of collapsin response mediator protein 2 at tyrosine 32. J Biol Chem. 2009 Oct 2;284(40):27393-401. Epub 2009 Aug 3. PMID:19652227 doi:M109.000240
- ↑ Goh YM, Cinghu S, Hong ET, Lee YS, Kim JH, Jang JW, Li YH, Chi XZ, Lee KS, Wee H, Ito Y, Oh BC, Bae SC. Src kinase phosphorylates RUNX3 at tyrosine residues and localizes the protein in the cytoplasm. J Biol Chem. 2010 Mar 26;285(13):10122-9. doi: 10.1074/jbc.M109.071381. Epub 2010, Jan 25. PMID:20100835 doi:10.1074/jbc.M109.071381
- ↑ Camara-Artigas A, Ortiz-Salmeron E, Andujar-Sanchez M, Bacarizo J, Martin-Garcia JM. The role of water molecules in the binding of class I and II peptides to the SH3 domain of the Fyn tyrosine kinase. Acta Crystallogr F Struct Biol Commun. 2016 Sep;72(Pt 9):707-12. doi:, 10.1107/S2053230X16012310. Epub 2016 Aug 26. PMID:27599862 doi:http://dx.doi.org/10.1107/S2053230X16012310
|
