Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_577


Historical Background

The adhesion and degranulation promoting adapter protein (ADAP) is a large protein which is alternatively spliced to produce a 120 or a 130 kDa isoform and is expressed in T cells, proB cells (but not mature B cells), and myeloid cells. ADAP was first cloned in 1997 by two independent labs that were working to elucidate signaling pathways induced by engagement of the T cell receptor. In early studies, the kinase, Fyn-T, was found to be an important mediator of mature, peripheral T cell activation. In order to identify potential substrates of Fyn-T, da Silva et al. used GST–FYN-SH2 domain fusion proteins to immunoprecipitate a 120/130 kDa phosphorylated protein from a TCR/antiCD3 stimulated T cell line. An antibody developed against this protein was used to screen a Jurkat cell line cDNA library and led to the cloning of ADAP. In the same year, Musci et al. used a chimeric surface protein bearing the extracellular and transmembrane domains from HLA-A2 and the SH2 domain from SLP-76, a known T cell integrin modulatory protein, to precipitate out ADAP from pervanadate-stimulated JA2/SLP-SH2 Jurkat T cells. The newly cloned proteins were named Fyn-binding protein (FYB) and SLP-76-associated protein of 130 kDa (SLAP-130), respectively. However, the name adhesion and degranulation promoting adapter protein, ADAP, was adopted in 2001. Another major milestone was achieved with the generation of chimeric and knockout ADAP mice (ADAP−/−) by Griffiths et al. and Peterson et al. and helped resolve some of the controversies related to ADAP function that had surfaced in studies with cell lines (Peterson 2003). In recent years, the elucidation of new ADAP domains and interaction partners has expanded the repertoire of functions attributed to ADAP that span from actin-regulatory roles in lymphocytes, macrophages, and platelets to regulation of mast cell degranulation, T cell proliferation, thymopoiesis, osteoclastogenesis, eosinophil survival, and integrin regulation (Engelmann et al. 2015; Wang and Rudd 2008).

ADAP Structure and Domains

The scaffolding function of the multidomain protein, ADAP, permits assembly of multimolecular complexes that promote its adhesive and proliferation augmenting functions. Human ADAP is alternatively spliced to yield a 783 or 803AA protein of 120 or 130 kDa. Full-length mouse ADAP is 819AA. The regulation of ADAP is likely to be complex due to the presence of several serine/threonine residues and lysine acetylation sites, two putative nuclear localization sequences (PKKKRKV) and 16 tyrosine phosphorylation sites, 13 of which are concentrated in the region between AA486 and 783 (Sylvester et al. 2010). Figure 1 highlights many of the domains that have been mapped to date. Two key interactions in T cells are (a) between ADAP proline-rich domain AA 338–358, that mediates association with SH3 domain-containing homologous adapter proteins, SKAP1 and SKAP2, and is necessary for ADAP-mediated SKAP protein stabilization, and (b) between a glutamic acid/lysine (E/K) rich region that recognizes the MAGUK binding domain of CARMA1, involved in NFKB activation. Downstream of this region is the first of two unusual helically extended SH3 domains (hSH3) that have lost the ability to bind the classical SH3 proline-rich recognition motif, but instead can associate with phospholipids (Heuer et al. 2004). Interposed between the hSH3 domains are the mid-protein tyrosines YEDI, two YDDV sequences, and YDGI, which are recognition sites for SH2 domains of FYN, NCK, and SLP-76, and a central FPPPP site that constitutes a VASP EVH1 binding domain. In mast cells, ADAP has been reported to bind the SH2 domain of the mast cell immunoreceptor signal transducer (MIST). Recent studies utilizing mass spectrometry and pull-downs of phospho-ADAP from chemokine stimulated T cells have indicated an association between the N-terminal SH2 domain of Zap-70 and ADAP Y571 in the SH3 helical domain, which affects T cell migration but not adhesion (Kuropka et al. 2015). Limited structural data exists for ADAP: Zimmerman et al. have demonstrated that the two cysteines in ADAP that are adjacent to the hSH3N domain can be reversibly oxidized and reduced in vitro and result in two distinct conformations of the variable arginine threonine loop (Zimmermann et al. 2007). A three-dimensional C-terminal domain NMR structure has been solved by Heuer et al. (Fig. 2) and depicts the hSH3 domain as a twisted β-sheet structure, with the N-terminal helical portion packed against the open side of the twisted sheet and contacting residues from the β-strands, thus forming an helically extended SH3 domain. In the very carboxy-terminus of ADAP, there are binding sites for TAK1 and SRC. In summary, the combinatorial binding possibilities that may exist depending on cell-specific expression of binding partners are complex and harbor potential for as yet undetermined functions.
ADAP, Fig. 1

ADAP binding domains. Adhesion and degranulation-promoting adapter protein (ADAP) is a 120/130 kDA protein that contains domains for scaffolding proteins of various classes, many of which are depicted here. The N-terminus harbors sites for monomeric actin binding protein (mABP1; also known as HIP55), and via proline-rich (Pro-rich) regions, to SH3 domains of the homologous SKAP adapter proteins, SKAP 1 and SKAP2 (also known as SKAP55 and SKAP-HOM). The central domain contains serine/threonine (S/T) and tyrosine (Y) residues whose phosphorylation regulates binding to SH2 domains of FYN, NCK, and SLP-76; an E/K rich region that binds the CARMA1 MAGUK domain; two putative nuclear localization sequences (NLS); an FPPPP EVH1 binding domain for VASP interactions; an alternative splice site of 46 AA; and two helically extended SH3 domains (hSH3) both of which bind phosphoinositols and C-SH3 binds the Yersinia phosphatase, YopH. At the carboxy terminus end are binding sites for the kinases TAK1 and SRC. Approximate amino acid residue locations are indicated. Putatitive association sites for talin and kindlin-3 are indicated in orange. Figure is not drawn to scale

ADAP, Fig. 2

Solution structures of the ADAP-hSH3 domain. (a) Ensemble of the final 20 structures of ADAP-hSH3 domain. Structures are superimposed over the backbone atoms (Cα, C′, N) of residues 7–83. (b) Ribbon diagram of the lowest energy structure of ADAP-hSH3 domain, produced by the program MOLMOL. Secondary structure elements typical for a regular SH3 fold comprise a β sheet barrel (strands ad), RT loop (between strand a and b), nSrc-loop (between strand b and c), and a 310 helix.α : α helix, ad: β strands ad. (c) Electrostatic surface potential calculated with the program MOLMOL highlighting key residues on the surface of the ADAP-hSH3 domain, in particular those of the N-terminal helix. (d) Residues at the interface of the helix and the SH3 domain fold. The backbone ribbon belonging to the regular SH3 fold is indicated in green, while the ribbon of the N-terminal extension is colored red. Side chains of residues of the extended N terminus and the regular SH3 fold are in blue and pale blue, respectively. Structures in (a) and (d) are shown as stereo images. This research was originally published in Structure (Heuer et al. 2004)

ADAP Role in Proliferation and Transcription

ADAP is important for T cell development and the generation of memory phenotype CD8+ T cells, and mice deficient in ADAP are hyperresponsive to lymphopenia in vivo (Fiege et al. 2015). While it was known that ADAP positively modulated T cell proliferation and cytokine production following stimulation of the T cell receptor (TCR), the relevant mechanisms remained unknown for some time. Medeiros et al. 2007, first described how ADAP may promote T-cell proliferation by supporting the activation and translocation of the transcription factor, NF-ΚB from cytoplasm to nucleus. ADAP interaction with caspase recruitment domain (CARD) membrane-associated protein 1 (CARMA1) promotes assembly of the CBM complex, CARMA1, Bcl-10, and MALT1, that is followed by recruitment of TAK1 to the IKK complex, phosphorylation and degradation of IKBα, and release of NFKB to transit from the cytoplasm to the nucleus for transcriptional activity. As expected, in ADAP−/− mice, activation of the NF-ΚB pathway is impaired and the CBM complex is mislocalized (Srivastava et al. 2010). Recombinant adenoviral constructs and ADAP−/− mice expressing the hCAR receptor (CD21 positive) were used to determine that the two sites on ADAP for TAK1 and CARMA1 operate independently, with the CARMA1 and TAK1 binding sites controlling IKKγ ubiquitination and IKK phosphorylation, respectively. As ADAP has been found to be necessary for thymopoiesis as well, it is possible that ADAP may yet have a further role in proliferation and differentiation, possibly by virtue of the putative nuclear localization signals that have been described but not yet mapped to specific functions.

ADAP Role in Integrin Regulation

Integrins are heterodimeric transmembrane proteins consisting of α and β subunits which are clasped in the resting state but can undergo conformational changes to upregulate their affinity for ligands, and cluster to increase avidity. Hematopoietic cells, whether involved in immune or hemostatic function, require high affinity and/or high avidity bonds to establish strong and stable cell-matrix interactions in order to allow them to withstand hydrodynamic stresses as they adhere to vascular walls, migrate, and transmigrate (diapedese). Activated αLβ2, LFA-1, plays a particularly important role in T cell function and is required for both conjugate formation with antigen presenting cells (APC) and stabilization of transient selectin-mediated interactions with inflamed vessel walls, through binding to ICAM 1, 2, or 3, expressed on endothelial cells or on APCs. It was first noted in T cells that overexpression of ADAP enhanced, and loss of ADAP from T cell lines and ADAP−/− mice decreased, TCR-induced integrin-dependent adhesion. Since the primary driving force for development of ADAP reagents and mice stemmed from interest in T cell physiology, mechanistic investigations into ADAP’s role in integrin activation were primarily derived from studies in this cell type (Witte et al. 2012; Jordan and Koretzky 2010; Wang and Rudd 2008). However, experimental evidence for an ADAP role in integrin affinity modulation in platelets and other myeloid lineage cells is similarly strong. Stimulation of T cells through the TCR activates LFA-1 through a signaling cascade initiated by ZAP-70 recruitment to tandem ITAM domains of the TCR and phosphorylation by p59Fyn-T, thereby activating its kinase function to promote phosphorylation of multiple proteins including SLP-76, SKAP1, phospholipase Cγ, and ADAP. As ADAP was found to be dispensable for TCR stimulated PLCγ phosphorylation and mitogen-activated protein kinase (MAPK) activation in the ADAP−/− mouse, further investigations focused on downstream signaling events. Several lines of evidence have pointed to a functional partnership between ADAP and SLP-76 for upregulation of integrin activation and adhesion, as mutations of ADAP tyrosines in the two YDDV sites that mediate SLP-76 binding lead to a loss of integrin clustering, T cell APC conjugate formation, and assembly of the peripheral supramolecular activation complex (pSMAC) in Jurkat cells. The discovery that ADAP was constitutively associated with SKAP1 and that ADAP absence led to an almost absolute loss of SKAP1 and its homologue SKAP2 in vitro and in vivo raised the question of which of the two proteins was responsible for the defects in integrin regulation observed in ADAP negative cells. Interestingly, SKAP1 knockout mouse T cells, where ADAP expression is normal, showed similar integrin activation defects as those observed in the ADAP−/− mouse. This suggested that SKAP1 appears to be the effector molecule of importance for integrin regulation, at least in T cells, with ADAP serving to relocalize SKAP1. However, SKAP1 is not needed for ADAP’s NFKB-related function.

Two overlapping models for integrin activation in T cells which incorporate the ADAP-SKAP1 module and SKAP1’s binding of a Rap1 binding protein, RapL, and Rap1-interacting adhesion molecule (RIAM) were proposed to explain their role in LFA-1 activation in T cells (Fig. 3). Talin is a 280 kDa protein consisting of a FERM domain-containing head region that binds the juxtamembrane region and the proximal NPXY motif on β-integrin cytoplasmic tails to release the heterodimeric α/β subunit clasp and stabilize the open, high-affinity form of the integrin extracellular ligand-binding domain. In some cell types, this may be aided by a 30 residue N-terminal fragment of (Rap1-GTP interacting adapter molecule) RIAM that directly binds talin and causes it to swing in towards the membrane. The ADAP-SKAP complex is linked to RIAM through a constitutive association between the SKAP-1 N-terminal and RIAM PH domains, and ADAP may serve as a chaperone to escort the effector molecules SKAP1/RIAM and Rap1 to the membrane (Kliche et al. 2006; Menasche et al. 2007). In support of this model, perturbation of the ADAP/SKAP1/RIAM association disrupts recruitment of active Rap1 to the membrane and integrin activation. Active Rap1 also has increased affinity for RapL, an integrin αL subunit binding protein. Interestingly, the SKAP1 N-terminal domain also inducibly binds the SARAH RapL carboxy-terminal coiled-coil domain with a 1:1 stoichiometry as shown by isothermal titration calorimetry (Raab et al. 2010), and this interaction may provide an additional mechanism for LFA-1 activation in T cells. TCR versus cytokine stimulation may promote divergent signaling pathways, however, as SLP-76 and ADAP function independently to promote integrin activation downstream of cytokine receptor CXCR4, unlike following TCR activation (Horn et al. 2009). A potential negative regulator of ADAP and SLP-76 signaling is the adapter protein HPK, which competes with ADAP for binding to SLP-76. (Patzak et al. 2010).
ADAP, Fig. 3

ADAP pathways to integrin activation in T cells and platelets. In T cells, stimulation through the TCR promotes binding of ZAP-70 to TCR ITAM domains, activation of its kinase activity, and phosphorylation of SLP-76. This induces the recruitment of several proteins, including ADAP, and its constitutively associated partner, SKAP1. The ADAP-SKAP1 module constitutively interacts with the Rap1 binding protein, RIAM, which in stimulated T cells can reorient the integrin activator talin, to upregulate integrin affinity for ligand. ADAP also helps drive the interaction of SKAP1 with its other partner, RapL, which can bind the αL subunit of LFA-1. However, in platelets, which lack SKAP1 expression, upon stimulation with a variety of platelet agonists, ADAP associates with talin and kindlin-3 to effect RIAM and SKAP2 independent platelet αIIbβ3 integrin activation

In light of the scaffolding function of ADAP for effectors SKAP1 and SLP-76, which are necessary components of signaling pathways to integrin activation in T cells, a similar role for ADAP in platelet integrin activation was hypothesized. Although stimulation of platelets with a collagen mimetic agonist identified ADAP in large complexes together with SKAP2 and SLP-76, no mechanistic data was derived and no direct link between ADAP and activation of αIIbβ3, the relevant platelet integrin crucial for platelet aggregation and spreading, was examined (Asazuma et al. 2000). In the course of investigating GPIb-IX-V receptor signaling pathways to integrin αIIbβ3 activation, Kasirer-Friede et al. discovered that ADAP underwent SRC-family kinase dependent phosphorylation. Subsequent studies using ADAP−/− mice clearly demonstrated a role for ADAP in αIIbβ3 activation downstream of several platelet agonists. The in vivo consequences of an ADAP deficiency were reflected by increased rebleeding in these mice when challenged by tail vein transection and by abnormal thrombus formation in the carotid artery upon chemical injury. Mechanistic studies revealed that, unlike the important integrin regulatory role for an ADAP-SKAP1 module in T cells, in platelets where only the SKAP2 homologue is expressed, surprisingly no integrin modulatory role could be ascribed to SKAP2, as evidenced by in vitro and vivo experiments with SKAP2 knockout mice (Kasirer-Friede et al. 2010). The similarly absent role for RIAM using knockout mouse platelets deduced from three separate studies highlighted differences in platelet integrin activation between T cells and platelets. Thus, the novel associations of ADAP domains AA 565-615 with talin and AA 180-295 and with kindlin-3, another key integrin proximal regulatory protein, described by Kasirer-Friede et al. (2014) provided an attractive alternative pathway for ADAP modulation of integrin activity in platelets. Overexpression of ADAP in mast cells also enhances β1 integrin-dependent adhesion and clustering and mast cell degranulation. Similarly, ADAP has been implicated in macrophage, neutrophil, eosinophil, and pre-osteoclast development and/or functions where integrin activation is allegedly important. Nevertheless, sufficient variation exists in cell-specific ADAP signaling pathways, that further studies are needed to identify relevant signaling pathways between upstream agonists and integrin activation that connect ADAP with appropriate binding partners in the context of specific cellular environments.

ADAP Regulation of the Cytoskeleton

Reorganization of the actin cytoskeleton in response to stimulus is necessary for interaction of T cells with antigen presenting cells (APC’s), phagocytosis by macrophages and platelet spreading. Microscopy and biochemical studies have revealed a consistent association between ADAP and cytoskeletal proteins that control actin polymerization in hematopoietic cells with distinct cell morphologies and underlying cytoskeletal networks (Peterson 2003; Wang and Rudd 2008). These studies indicate that ADAP may be found in large molecular complexes associated with SLP-76, NCK, VASP, and Arp2/3, which individually and together, bind exchange factors and adapters to promote cytoskeletal reorganization. Furthermore, ADAP was shown to directly interact with VASP by screening a mouse embryonic expression library with antibodies against the VASP EVH1 domain binding motif, and with NCK, by yeast two-hybrid analysis (Sylvester et al. 2010). In T cells, a highly organized region composed of integrins, TCR, and many other signaling and structural proteins is formed between T cells and APCs and is referred to as the immunological synapse (IS). The ADAP/VASP interaction helps recruit VASP to the IS, and inhibition of the ADAP and Ena/VASP association impairs T cell polarization and formation of an actin cap at the T cell/APC junction. IS assembly is preceded by microclustering of several molecules including SLP-76, ZAP70, and Linker for Activation of T cells (LAT) that relocalize to the vicinity of the T cell/APC interface at the membrane, events that occur independently of integrin clustering. Not surprisingly, primary T cells lacking ADAP are unable to relocalize SLP-76 to microclusters. ADAP is additionally subject to dephosphorylation by SHP2 in response to increased cellular redox potential upon TCR stimulation, and may dampen ADAP-mediated cytoskeletal reorganization.

Upon CD3/CD28 stimulation of the T cell receptor (TCR), LFA-1 becomes activated. TCRs are eventually encircled by peripheral, activated LFA-1 clusters to form a highly organized supramolecular activation complex, which becomes a hub for many signaling molecules. Although ADAP is not needed for the immediate actin reorganization and TCR clustering, ADAP is necessary for clustering of LFA-1, a process that is actin dependent, as it is abrogated by cytocholasin D. ADAP regulation of β1 integrin clustering has also been demonstrated in mast cells.

LFA-1 dependent T cell migration is required for T cell mobilization to sites of inflammation, to and within lymph nodes, and for transmigration through high endothelial venules. ADAP overexpression can increase migration in Jurkat T cells (Witte et al. 2012). The case for an ADAP role in T cell migration is manifold: (1) ADAP expression in T cell blasts increased α4β1 mediated basal migration through fibronectin-coated transwells, and further enhanced migration speeds over those in untransfected cells when stimulated with the CXCR4 ligand, SDF-1α. (2) Mutation of ADAP tyrosines Y755, Y771, and Y780 within the hSH3 domain, to phenylalanine, led to decreased SDF-1α-induced migration of Jurkat cells through a transwell chamber. However, double mutation of the SLP-76 binding sites, Y595 and Y651, produced the greatest reduction in SDF-1α induced migration. (3) In contrast, OVA peptide presentation on dendritic cells in lymph node slices decreased T cell mobility, in a manner dependent on an intact binding interface between ADAP/SKAP1 and RapL (Raab et al. 2010).

In platelets, under static no flow conditions, ADAP is found at the periphery of platelets spread on fibrinogen. However, under shear flow conditions with hydrodynamic shear stresses acting on adhering platelets, the actin cytoskeleton is preferentially organized into actin-rich microclusters that are spatially distributed throughout the platelet together with ADAP (Fig. 4a) and other proteins, including VAV, SLP-76, VASP, and the focal adhesion constituent, vinculin (Fig. 5).
ADAP, Fig. 4

ADAP in platelet adhesion to fibrinogen under shear flow conditions. Flow chamber assay of platelets adhering from whole blood onto fibrinogen-coated coverslips at a shear rate of 500 s1. (a) Platelets were perfusion-fixed after 1.5 min of flow, permeabilized, and stained for F-actin (red) and ADAP (blue). Actin-rich structures containing ADAP form in wild-type platelets adherent to fibrinogen but are greatly reduced in ADAP−/− platelets. A line profile shows almost identical localization of actin and ADAP fluorescence distribution in representative ADAP+/+ platelets. (b, c) Identical ADAP+/+ or ADAP−/− blood suspensions were either perfused over fibrinogen under shear flow at 500 s1 (b) or pre-treated with MnCl2, an extrinsic integrin activator, and gently applied to fibrinogen-coated coverslips within the flow chamber under static conditions (c), and continuously imaged by reflection interference contrast microscopy for 3 min. Images shown are after 1.5 min of blood exposure to the matrix. Well-spread platelets are observed for both strains under static conditions, but only for ADAP+/+ under shear flow, even when cells are treated with MnCl2 (not shown). This research was originally published in Blood (Kasirer-Friede et al. 2010. © the American Society of Hematology)

ADAP, Fig. 5

Live videomicroscopy was used to demonstrate that in ADAP−/− platelets, spreading and cluster assembly is greatly reduced under shear flow (Fig. 5, Fig. 4b, c) (Kasirer-Friede et al. 2010). Furthermore, the phosphorylation of VAV, which occurs in response to shear stimulation, is almost completely absent in ADAP−/− mouse platelets. These studies led to a hypothesized role for ADAP in platelet mechanotransduction, mediated at least in part through its regulation of phospho-VAV activation of RAC for lamellipodia formation. ADAP may additionally mediate normal platelet responses under shear flow by additional, thus far unidentified, mechanisms

In the macrophage, whose engulfment of pathogens contributes to immune defense, ADAP localizes to membrane ruffles and plaques and at sites of phagocytosis along with actin. ADAP associates with actin regulatory proteins SLP-76, NCK, and VASP as in T cells, as well as with the C-terminal SH3 domain of mAbp1. Thus, its multiple interaction nodes place ADAP in a strong position to modulate cytoskeletal dynamics. The human pathogenic Yersinia bacterial species have evolved mechanisms to interfere with phagocytosis by injection of the phosphatases, YopH and YopE, that interestingly can target SKAP2 and ADAP as well as other proteins, leading to their dephosphorylation and reduced phagocytosis (de la Puerta et al. 2009). ADAP/SKAP2 can also complex with macrophage inhibitory receptors SHPS-1 and SHP-1 via the SKAP2 SH3 domain, and mice lacking SHP-1 show increased p120/ADAP phosphorylation. In macrophage-like pre-osteoblasts, which also express ADAP, integrin-dependent tyrosine phosphorylation of ADAP occurs, and ADAP knockdown retards migration and progression to the multinucleate stage (Koga et al. 2005). Taken together, this suggests that in macrophages ADAP phosphorylation state may be one of the factors regulating its interactions with actin and actin regulatory proteins.

ADAP Relevance to Human Patients and in Disease Models

Only a handful of studies have attempted to investigate ADAP’s role in human patients, but some correlation between ADAP expression or integrity with hemostastic or immune deficiency has been identified, thereby in part substantiating previous mouse studies (Engelmann et al. 2015). The most revealing thus far have been two studies of patients of Middle Eastern descent from consanguineous families, exhibiting petechial rashes accompanied by a bleeding tendency. Causative mutations in the Fyb gene were identified: a C.393G>A mutation in one group of families and a frameshift mutation leading to a premature stop codon at c.1385_1386 del: p(Tyr462) in the other. Like ADAP−/− mice, patients were thrombocytopenic; however, human patient platelets were also reduced in volume (Hamamy et al. 2014; Levin et al. 2015). In contrast, no role for ADAP in Type I diabetes in Brazilian patients was found, despite data from mouse models of autoimmune diabetes indicating a protective effect of ADAP. In another T-cell driven disease, an increase in ADAP levels has been correlated with susceptibility to systemic lupus erythomatous (SLE). Furthermore, ADAP was one of the 17/240 genes that when upregulated indicated a poor prognosis in patients with the T cell lymphoma, cutaneous mycosis fungoides (Litvinov et al. 2015). Thus, ADAP appears to mostly augment rather than diminish immune disorders driven by T cell hyperfunction in humans. In mice, absence of ADAP ameliorated survival in tests of heart and intestinal allograft transplants, reflecting ADAP’s role in T-cell mediated immunity. The role of ADAP specifically in CD8+ T cell function in pathogen clearance has been tested in mice with inconclusive results. In one study, by Li et al., loss of ADAP in mice led to increased Influenza virus A-induced mortality, whereas in another study, the ability of ADAP−/− CD8+ T cells to clear similar infection was unimpaired (Parzmair et al. 2017). Finally, the ADAP/SKAP1 module can reduce cytotoxicity of CD8+ T cells through positive regulation of the inhibitory molecule, PD-1. Thus, ADAP may be an interesting target for immune therapeutics, especially if CD4 and CD8 T cells turn out to indeed differentially depend on ADAP for their immune function.


Although ADAP was only cloned less than two decades ago, studies have repeatedly detailed an important role for this protein in regulation of proliferation, adhesion, and cellular development. Although studies thus far have provided important insights into how ADAP interfaces with its binding partners, more work is required to identify novel regulatory mechanisms for the as yet “unassigned” residues such as serines and lysines that may be subject to post-translational modifications within individual cellular environments to effect cell-specific functions. New studies likely will continue to expand the repertoire of ADAP binding partners and increase the understanding of how its numerous and diverse domains are regulated. In the coming era, ADAP mutations may be mapped specifically to hemostastatic and thrombotic defects or to perturbed immune function. Additionally, as the signaling pathways linking ADAP to integrin activation differ for platelets and leukocytes, it is potentially a molecular target for therapeutics that seek to selectively disrupt its immune versus hemostatic function. Therefore, it will be interesting to see how basic research studies on ADAP can be translated into health benefits for human patients.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of California, San DiegoLa JollaUSA