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 FYBgene in humans.[5] The protein is expressed in T cells, monocytes, mast cells, macrophages, NK cells, but not B cells.[6][7][8][9] FYB is a multifunctional protein involved in post-activation T cell signaling, lymphocyte cytokine production, cell adhesion, and actin remodeling.[7][8][9][10][11]
Structure
Two isoforms of FYB with different lengths of 120 and 130 kDa (FYB-120 and FYB-130) exist.[8] The 130kDa version has an extra insertion of 46 amino acids and is preferentially expressed in peripheral T cells.[8] 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.[11]
FYB regulates cytokine production in T cells as well as in activated NK cells through the FYN-ADAP axis.[9] In T cells, after TCR stimulation, a unique region of FYB, pYDGI, allows phosphorylation of the protein by FYN.[9] After being phosphorylated, ADAP can bind to Carma1, causing NF-κB translocation into the nucleus and cytokine production.[9]
In mast cells, FYB regulates cell adhesion as well as degranulation.[7] In T cells, FYB allows for cell adhesion and migration through blood vessels through the SLP-76-FYB-SKAP1 complex.[10] After being phosphorylated by FYN, FYB can bind to SLP-76.[7] 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.[10] FYB can also bind to SKAP1, which allows SKAP1 to upregulate integrin activity through interactions with Rap1.[8][10] 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.[8]
FYB is also an important protein for actin remodeling of immune cells.[11] This is thought to occur through the binding of proteins of the ENA/VASP protein family to the FPPPP-motif of the FYB protein.[11]
^Schraven B, Marie-Cardine A, Koretzky G (June 1997). "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. doi:10.1016/s0165-2478(97)00053-9. PMID9232446.
^ abcdGriffiths EK, Penninger JM (June 2002). "Communication between the TCR and integrins: role of the molecular adapter ADAP/Fyb/Slap". Current Opinion in Immunology. 14 (3): 317–322. doi:10.1016/s0952-7915(02)00334-5. PMID11973129.
Marie-Cardine A, Verhagen AM, Eckerskorn C, Schraven B (September 1998). "SKAP-HOM, a novel adaptor protein homologous to the FYN-associated protein SKAP55". FEBS Letters. 435 (1): 55–60. doi:10.1016/S0014-5793(98)01040-0. PMID9755858. S2CID37288744.
Hamid N, Gustavsson A, Andersson K, McGee K, Persson C, Rudd CE, Fällman M (October 1999). "YopH dephosphorylates Cas and Fyn-binding protein in macrophages". Microbial Pathogenesis. 27 (4): 231–242. doi:10.1006/mpat.1999.0301. PMID10502464.
Geng L, Raab M, Rudd CE (December 1999). "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. PMID10570256.
Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC (May 2004). "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. doi:10.1021/ac035352d. PMID15144186.
Heuer K, Arbuzova A, Strauss H, Kofler M, Freund C (May 2005). "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. doi:10.1016/j.jmb.2005.02.069. PMID15843031.
