Tyrosine-phosphorylation of the scaffold protein ADAP and its role in T cell signaling

Abstract

This article reviews current knowledge of the functions of the adapter protein ADAP in T cell signaling with a focus on the role of individual phosphotyrosine (pY) motifs for SH2 domain mediated interactions. The data presented was obtained from literature searches (PubMed) as well as the authors own research on the topic. Expert commentary: ADAP can be regarded as a paradigmatic example of how tyrosine phosphorylation sites serve as dynamic interaction hubs. Molecular crowding at unstructured and redundant sites (pY595, pY651) is contrasted by more specific interactions enabled by the three-dimensional environment of a particular phosphotyrosine motif (pY571).

The Multiple Roles of the Cytosolic Adapter Proteins ADAP, SKAP1 and SKAP2 for TCR/CD3 -Mediated Signaling Events

“…ADAP and Ubc9: A New Player for TCR/ CD3-Mediated LFA-1 Activation ADAP was the first adapter protein identified that is involved in TCR/CD3-induced inside-out and outside-in signaling events of LFA-1 (27,(65)(66)(67). Recently, Ubc9, the small ubiquitin-related modifier (SUMO) E2 conjugase was identified as an inducible binding partner of ADAP (83).…”

“…ADAP [alias SLAP-130 (SLP-76-associated protein of 130kDa(60)], or FYB [Fyn-binding protein(63)] is expressed in thymocytes, peripheral T cells and other hematopoietic cells [for review please see(64)]. As depicted in Figure2, ADAP possess a non-structured N-terminal region, a proline-rich region (PRR), two helical SH3 (Src homology 3) domains, a FPPPP-motif that mediates binding to members of the Ena (Enabled)/VASP (Vasodilator-stimulated Phosphoprotein) family and several tyrosine-based signaling motifs [for review please see(65)]. Knockout and knockdown studies had shown early on that ADAP is a positive regulator of T-cell development, TCR/CD3-induced T-cell activation (CD69/CD25 upregulation), IL-2 and IFN-g production, proliferation and LFA-1 affinity/ avidity regulation [for reviews please see(27,(64)(65)(66)(67)].…”

ADAP’s intrinsically disordered region is an actin sponge regulating T cell motility

“…The overexpressed proteins were purified as described above and measurements were performed in 10mM HEPES, 50mM NaCl, pH 6.5 with 10% D2O. HNCA, HN(CO)CA, HNCO, HN(CA)CO, HNCACB spectra were recorded at 300K for 500µM 13 C-15 N-labeled ADAP1-100. HNCA, HN(CO)CA, HNCO, HN(CA)CO, HNCACB, (H)N(CA)NH spectra were recorded at 300K and HNCA, HN(CO)CA, (H)N(CA)NH were recorded at 280K for 400µM 13 C-15 N-labeled ADAP100-200.…”

“…ADAP does not interact directly with the TCR, chemokine receptors or integrins, yet it constitutes the common signaling component connecting these receptors. Two atypical hSH3 domains confer weak lipid binding 9 and activation-dependent phosphorylation of the interdomain linker engages SH2 domain-containing kinases and adaptor proteins [10][11][12][13][14][15] . While ADAP was found to co-localize with actin-rich patches in lamellipodia of Jurkat cells 16 and is linked to the actin regulators Ena/VASP and Nck 17,18 , it's conceivable role as a driver of actin dynamics has not been addressed.…”

Effects of fostriecin on β2-adrenoceptor-driven responses in human mast cells

“…Protein phosphatases that dephosphorylate either tyrosine or serine and threonine constitute the two main families and are referred to as protein tyrosine phosphatases (PTP) and protein serine/threonine phosphatase (PP), respectively (Cohen et al 1991). Protein tyrosine phosphatases form a large family of still largely uncharacterized enzymes (Kuropka et al 2016). The level of tyrosine phosphorylation in normal cells is determined by the balanced activity of protein tyrosine kinases (PTK) and PTP.…”