FYB explained

FYN binding protein (FYB-120/130), also known as FYB, ADAP (Adhesion and degranulation-promoting adapter protein), and SLAP-130 (SLP-76-associated phosphoprotein) is a protein that is encoded by the FYB gene in humans.^[1] The protein is expressed in T cells, monocytes, mast cells, macrophages, NK cells, but not B cells.^{[2] [3] [4] [5]} FYB is a multifunctional protein involved in post-activation T cell signaling, lymphocyte cytokine production, cell adhesion, and actin remodeling.^{[6] [7]}

Structure

Two isoforms of FYB with different lengths of 120 and 130 kDa (FYB-120 and FYB-130) exist. The 130kDa version has an extra insertion of 46 amino acids and is preferentially expressed in peripheral T cells. The FYB protein has a variety of binding domains: a non-structured N-terminal region, a proline-rich region, two SH3 domains, a FPPP-motif which binds the ENA/VASP protein family, and other tyrosine-based signaling motifs.

Function

FYB is critical for activation and proliferation of T-helper cells (CD4+) and required for chemokine signal transduction in T-helper cells and cytotoxic T cells (CD8+).

FYB regulates cytokine production in T cells as well as in activated NK cells through the FYN-ADAP axis. In T cells, after TCR stimulation, a unique region of FYB, pYDGI, allows phosphorylation of the protein by FYN. After being phosphorylated, ADAP can bind to Carma1, causing NF-κB translocation into the nucleus and cytokine production.

In mast cells, FYB regulates cell adhesion as well as degranulation. In T cells, FYB allows for cell adhesion and migration through blood vessels through the SLP-76-FYB-SKAP1 complex. After being phosphorylated by FYN, FYB can bind to SLP-76. This binding of FYB and SLP-76 regulates "outside-in signaling" or the transfer of signals from outside the cell to inside the cell by integrin. FYB can also bind to SKAP1, which allows SKAP1 to upregulate integrin activity through interactions with Rap1. The bacteria Yersinia can interfere with this pathway in macrophages through the secretion of YopH (Yersinia protein tyrosine phosphatase) into the macrophage, which de-phosphorylates FYB and SKAP1, leading to a decrease in integrin activity that results in an inhibition of adhesion, phagocytosis, and cytotoxicity.

FYB is also an important protein for actin remodeling of immune cells. This is thought to occur through the binding of proteins of the ENA/VASP protein family to the FPPPP-motif of the FYB protein.

Further reading

• da Silva AJ, Janssen O, Rudd CE . T cell receptor zeta/CD3-p59fyn(T)-associated p120/130 binds to the SH2 domain of p59fyn(T) . The Journal of Experimental Medicine . 178 . 6 . 2107–2113 . December 1993 . 7504057 . 2191307 . 10.1084/jem.178.6.2107 .
• Musci MA, Hendricks-Taylor LR, Motto DG, Paskind M, Kamens J, Turck CW, Koretzky GA . Molecular cloning of SLAP-130, an SLP-76-associated substrate of the T cell antigen receptor-stimulated protein tyrosine kinases . The Journal of Biological Chemistry . 272 . 18 . 11674–11677 . May 1997 . 9115214 . 10.1074/jbc.272.18.11674 . free .
• da Silva AJ, Li Z, de Vera C, Canto E, Findell P, Rudd CE . Cloning of a novel T-cell protein FYB that binds FYN and SH2-domain-containing leukocyte protein 76 and modulates interleukin 2 production . Proceedings of the National Academy of Sciences of the United States of America . 94 . 14 . 7493–7498 . July 1997 . 9207119 . 23849 . 10.1073/pnas.94.14.7493 . free . 1997PNAS...94.7493D .
• Liu J, Kang H, Raab M, da Silva AJ, Kraeft SK, Rudd CE . FYB (FYN binding protein) serves as a binding partner for lymphoid protein and FYN kinase substrate SKAP55 and a SKAP55-related protein in T cells . Proceedings of the National Academy of Sciences of the United States of America . 95 . 15 . 8779–8784 . July 1998 . 9671755 . 21153 . 10.1073/pnas.95.15.8779 . free . 1998PNAS...95.8779L .
• Marie-Cardine A, Hendricks-Taylor LR, Boerth NJ, Zhao H, Schraven B, Koretzky GA . Molecular interaction between the Fyn-associated protein SKAP55 and the SLP-76-associated phosphoprotein SLAP-130 . The Journal of Biological Chemistry . 273 . 40 . 25789–25795 . October 1998 . 9748251 . 10.1074/jbc.273.40.25789 . free .
• Marie-Cardine A, Verhagen AM, Eckerskorn C, Schraven B . SKAP-HOM, a novel adaptor protein homologous to the FYN-associated protein SKAP55 . FEBS Letters . 435 . 1 . 55–60 . September 1998 . 9755858 . 10.1016/S0014-5793(98)01040-0 . 37288744 . free .
• Veale M, Raab M, Li Z, da Silva AJ, Kraeft SK, Weremowicz S, Morton CC, Rudd CE . 6 . Novel isoform of lymphoid adaptor FYN-T-binding protein (FYB-130) interacts with SLP-76 and up-regulates interleukin 2 production . The Journal of Biological Chemistry . 274 . 40 . 28427–28435 . October 1999 . 10497204 . 10.1074/jbc.274.40.28427 . free .
• Hamid N, Gustavsson A, Andersson K, McGee K, Persson C, Rudd CE, Fällman M . YopH dephosphorylates Cas and Fyn-binding protein in macrophages . Microbial Pathogenesis . 27 . 4 . 231–242 . October 1999 . 10502464 . 10.1006/mpat.1999.0301 .
• Geng L, Raab M, Rudd CE . Cutting edge: SLP-76 cooperativity with FYB/FYN-T in the Up-regulation of TCR-driven IL-2 transcription requires SLP-76 binding to FYB at Tyr595 and Tyr651 . Journal of Immunology . 163 . 11 . 5753–5757 . December 1999 . 10.4049/jimmunol.163.11.5753 . 10570256 . 29719649 . free .
• Krause M, Sechi AS, Konradt M, Monner D, Gertler FB, Wehland J . Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton . The Journal of Cell Biology . 149 . 1 . 181–194 . April 2000 . 10747096 . 2175102 . 10.1083/jcb.149.1.181 .
• Kang H, Freund C, Duke-Cohan JS, Musacchio A, Wagner G, Rudd CE . SH3 domain recognition of a proline-independent tyrosine-based RKxxYxxY motif in immune cell adaptor SKAP55 . The EMBO Journal . 19 . 12 . 2889–2899 . June 2000 . 10856234 . 203341 . 10.1093/emboj/19.12.2889 .
• Asazuma N, Wilde JI, Berlanga O, Leduc M, Leo A, Schweighoffer E, Tybulewicz V, Bon C, Liu SK, McGlade CJ, Schraven B, Watson SP . 6 . Interaction of linker for activation of T cells with multiple adapter proteins in platelets activated by the glycoprotein VI-selective ligand, convulxin . The Journal of Biological Chemistry . 275 . 43 . 33427–33434 . October 2000 . 10942756 . 10.1074/jbc.M001439200 . free .
• Li C, Iosef C, Jia CY, Han VK, Li SS . Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors . The Journal of Biological Chemistry . 278 . 6 . 3852–3859 . February 2003 . 12458214 . 10.1074/jbc.M206649200 . free .
• Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC . Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry . Analytical Chemistry . 76 . 10 . 2763–2772 . May 2004 . 15144186 . 10.1021/ac035352d .
• Heuer K, Arbuzova A, Strauss H, Kofler M, Freund C . The helically extended SH3 domain of the T cell adaptor protein ADAP is a novel lipid interaction domain . Journal of Molecular Biology . 348 . 4 . 1025–1035 . May 2005 . 15843031 . 10.1016/j.jmb.2005.02.069 .
• Huang Y, Norton DD, Precht P, Martindale JL, Burkhardt JK, Wange RL . Deficiency of ADAP/Fyb/SLAP-130 destabilizes SKAP55 in Jurkat T cells . The Journal of Biological Chemistry . 280 . 25 . 23576–23583 . June 2005 . 15849195 . 10.1074/jbc.M413201200 . free .
• Koga S, Yogo K, Yoshikawa K, Samori H, Goto M, Uchida T, Ishida N, Takeya T . 6 . Physical and functional association of c-Src and adhesion and degranulation promoting adaptor protein (ADAP) in osteoclastogenesis in vitro . The Journal of Biological Chemistry . 280 . 36 . 31564–31571 . September 2005 . 16020549 . 10.1074/jbc.M502703200 . free .
• Duke-Cohan JS, Kang H, Liu H, Rudd CE . Regulation and function of SKAP-55 non-canonical motif binding to the SH3c domain of adhesion and degranulation-promoting adaptor protein . The Journal of Biological Chemistry . 281 . 19 . 13743–13750 . May 2006 . 16461356 . 10.1074/jbc.M508774200 . free .

Notes and References

1. Web site: Entrez Gene: FYB FYN binding protein (FYB-120/130).
2. Schraven B, Marie-Cardine A, Koretzky G . Molecular analysis of the fyn-complex: cloning of SKAP55 and SLAP-130, two novel adaptor proteins which associate with fyn and may participate in the regulation of T cell receptor-mediated signaling . Immunology Letters . 57 . 1–3 . 165–169 . June 1997 . 9232446 . 10.1016/s0165-2478(97)00053-9 .
3. Griffiths EK, Penninger JM . Communication between the TCR and integrins: role of the molecular adapter ADAP/Fyb/Slap . Current Opinion in Immunology . 14 . 3 . 317–322 . June 2002 . 11973129 . 10.1016/s0952-7915(02)00334-5 .
4. Wang H, Rudd CE . SKAP-55, SKAP-55-related and ADAP adaptors modulate integrin-mediated immune-cell adhesion . Trends in Cell Biology . 18 . 10 . 486–493 . October 2008 . 18760924 . 10.1016/j.tcb.2008.07.005 . 3512129 .
5. Gerbec ZJ, Thakar MS, Malarkannan S . The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells . Frontiers in Immunology . 6 . 472 . 2015-09-16 . 26441977 . 10.3389/fimmu.2015.00472 . 4584950 . free .
6. Zhang Y, Wang H . Integrin signalling and function in immune cells . Immunology . 135 . 4 . 268–275 . April 2012 . 22211918 . 10.1111/j.1365-2567.2011.03549.x . 3372743 .
7. Dadwal N, Mix C, Reinhold A, Witte A, Freund C, Schraven B, Kliche S . The Multiple Roles of the Cytosolic Adapter Proteins ADAP, SKAP1 and SKAP2 for TCR/CD3 -Mediated Signaling Events . Frontiers in Immunology . 12 . 703534 . 2021-07-06 . 34295339 . 10.3389/fimmu.2021.703534 . 8290198 . free .