title: ADAP regulates cell cycle progression of T cells via control of cyclin E and Cdk2 expression through two distinct CARMA1-dependent signaling pathways.
abstract: Adhesion and degranulation-promoting adapter protein (ADAP) is a multifunctional scaffold that regulates T cell receptor-mediated activation of integrins via association with the SKAP55 adapter and the NF-κB pathway through interactions with both the CARMA1 adapter and serine/threonine kinase transforming growth factor β-activated kinase 1 (TAK1). ADAP-deficient T cells exhibit impaired proliferation following T cell receptor stimulation, but the contribution of these distinct functions of ADAP to this defect is not known. We demonstrate that loss of ADAP results in a G₁-S transition block in cell cycle progression following T cell activation due to impaired accumulation of cyclin-dependent kinase 2 (Cdk2) and cyclin E. The CARMA1-binding site in ADAP is critical for mitogen-activated protein (MAP) kinase kinase 7 (MKK7) phosphorylation and recruitment to the protein kinase C θ (PKCθ) signalosome and subsequent c-Jun kinase (JNK)-mediated Cdk2 induction. Cyclin E expression following T cell receptor stimulation of ADAP-deficient T cells is transient and associated with enhanced cyclin E ubiquitination. Both the CARMA1- and TAK1-binding sites in ADAP are critical for restraining cyclin E ubiquitination and turnover independently of ADAP-dependent JNK activation. T cell receptor-mediated proliferation was most dramatically impaired by the loss of ADAP interactions with CARMA1 or TAK1 rather than SKAP55. Thus, ADAP coordinates distinct CARMA1-dependent control of key cell cycle proteins in T cells.
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Rupa
authors.initials: R
authors.lastname: Srivastava
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Burbach
authors.forename: Jason S
authors.initials: JS
authors.lastname: Mitchell
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Pagán
authors.forename: Yoji
authors.initials: Y
authors.lastname: Shimizu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; D019927:Cyclin E; C491468:Fyb protein, mouse; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; C426242:CARD11 protein, human; D006162:Guanylate Cyclase