ADAP Regulates Cell Cycle Progression of T Cells via Control of Cyclin E and Cdk2 Expression through Two Distinct CARMA1-Dependent Signaling Pathways

Abstract

T lymphocyte activation requires physical contact with an antigen-presenting cell and the propagation of signals from the antigen-specific T cell receptor (TCR) that result in proliferation and differentiation. Adapter proteins coordinate the assembly of signalosomes that are essential for optimal T cell activation (36). In T cells, adhesion and degranulation-promoting adapter protein (ADAP) positively regulates T cell receptor signaling by facilitating the activation of integrin receptors that enhances T cell contact with antigen-presenting cells and by promoting the activation of 5,16,24,28,38,46). These two functions of ADAP are controlled by biochemically and functionally distinct pools of ADAP that are defined by SKAP55, another adapter that constitutively associates with a subset of the total ADAP expressed in a T cell (4, 5). The pool of ADAP associated with SKAP55 regulates integrin function, while the pool of ADAP not associated with SKAP55 regulates NF-B via TCR-inducible association with the CARMA1 adapter and the serine/threonine kinase transforming growth factor ␤-activated kinase 1 (TAK1) (4, 5, 24, 38). These inducible interactions facilitate the formation of the CARMA1-Bcl10-Malt1 (CBM) complex and the assembly of the protein kinase C (PKC) signalosome that are required for optimal T cell receptor-mediated activation of NF-B (42). Three discrete sites in ADAP mediate the association of ADAP with SKAP55, CARMA1, and TAK1 (24, 38). T cells lacking ADAP exhibit impaired TCR-mediated proliferation (16,27,28), but the contribution of these individual protein interactions with ADAP to this proliferative defect remains undefined.The successful progression of T cells through the cell cycle following TCR stimulation involves the temporal induction and activation of cyclins and cyclin-dependent kinases (Cdk's) (47). D-type cyclins, Cdk4, and Cdk6 are induced during the G 1 phase of the cell cycle, followed by the induction of cyclin E and the induction and activation of Cdk2 at the late G 1 restriction point.Expression of cyclin E is controlled by transcriptional regulation of cyclin E as well as by ubiquitin-dependent degradation of cyclin E. Both the cullin-3 E3 ubiquitin ligase (6, 37) and the SCF Fbw7 E3 ubiquitin ligase control cyclin E levels in a manner that is dependent on cyclin E phosphorylation and the association of cyclin E with Cdk2 (20,25,40,48). The signaling pathways that control the induction of cell cycle regulatory proteins in T cells remain incompletely characterized. NF-B has been implicated in the activation of cyclin D1 and cyclin A transcription, and IB kinase (IKK) has been proposed to play a role in cell cycle regulation (1,13,18,19,21,30). The c-Jun kinase (JNK) signaling pathway has also been reported to regulate cell cycle progression of multiple cell types. In fibroblasts, the JNK1 and JNK2 isoforms differentially regulate G 1 -S-phase transition and cell cycle progression via c-Jun, a downstream target of JNK (34). Similar differential functions for JNK1 and JNK2 have also b...

Negative Regulation of Memory Phenotype CD8 T Cell Conversion by Adhesion and Degranulation–Promoting Adapter Protein

“…The ADAP-SKAP55 signaling module is critical for TCR-mediated activation of integrin-mediated adhesion with APCs (12, 13). A second pool of ADAP is not associated with SKAP55, but activates NF-κB and JNK in a TCR-inducible manner (12, 14–16). …”

Dysregulation of the antigen-induced NF-κB signaling pathway in the development of human B-cells lymphomas

“…Recent studies have established that PDK1 is critical for efficient activation of PKCθ in T cells and PKCβ in B cells by the PI3K pathway. PDK1 is also required for the subsequent assembly of the CBM complex to activate NF-κB during coordinated stimulation of the TCR and co-stimulatory receptor CD28 or during activation of the BCR [57][58][59]. PDK1 phosphorylates PKCθ and has a dual role in TCR-mediating NF-κB activation by recruiting PKCθ and CARMA1 into lipid rafts [60].…”

“…Using B-cell specific conditional PDK1 knock-out mice (Table 1) and chemical inhibitor approaches, it was demonstrated that PDK1 plays a critical role in B-cells by promoting transduction of the BCR signalings that are essential for the activation of both NF-κB and Foxo transcription factors. PDK1 is required for the survival of resting and activated B cells through the activation of Foxo and NF-κB respectively [57].…”

Adhesion- and Degranulation-Promoting Adapter Protein Promotes CD8 T Cell Differentiation and Resident Memory Formation and Function during an Acute Infection

“…ADAP positively regulates both T-APC interactions and NF-κB and JNK transcriptional pathways (9, 13–17). A fraction of ADAP is constitutively associated with Src kinase-associated phosphoprotein of 55 kDa (SKAP55) (18).…”

“…ADAP not associated with SKAP55 positively regulates the activation of NF-κB and JNK in a TCR-inducible manner (15–18). The downstream effects of TCR-inducible interactions of ADAP with caspase recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA-1) and, transforming growth factor-β (TGF-β)-activated protein kinase (TAK-1) promote T cell entry into the cell cycle (9, 15–17). The ADAP-CARMA-1-TAK-1 signalosome is also required for cytokine and chemokine production by NK cells after NKG2D or CD137 stimulation (20).…”