STAP-2 interacts with Pyk2 and enhances Pyk2 activity in T-cells

Saitoh, Kunimasa; Tsuchiya, Takuya; Kashiwakura, Jun‐ichi; Muromoto, Ryuta; Kitai, Yuichi; Sekine, Yoshifumi; Oritani, Kenji; Matsuda, Tadashi

doi:10.1016/j.bbrc.2017.05.010

Cited by 14 publications

(13 citation statements)

References 32 publications

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“…STAP-2 contains four putative tyrosine phosphorylation sites at residues 22, 250, 310, and 322, and phosphorylation of Tyr250 plays an important role in some STAP-2 functions (11,25). To evaluate the effects of LCK on STAP-2 phosphorylation, we analyzed a series of STAP-2 YF mutants, in which each tyrosine residue of STAP-2 was individually substituted with a phenylalanine residue, in LCK-transfected 293T cells (Fig.…”

Section: Phosphorylation Of Stap-2 At Tyr250 By Lck Is Required To Re...mentioning

confidence: 99%

STAP-2 Is a Novel Positive Regulator of TCR-Proximal Signals

Saitoh

Kashiwakura

Kagohashi

et al. 2022

The Journal of Immunology

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TCR ligation with an Ag presented on MHC molecules promotes T cell activation, leading to the selection, differentiation, and proliferation of T cells and cytokine production. These immunological events are optimally arranged to provide appropriate responses against a variety of pathogens. We here propose signal-transducing adaptor protein-2 (STAP-2) as a new positive regulator of TCR signaling. STAP-2–deficient T cells showed reduced, whereas STAP-2–overexpressing T cells showed enhanced, TCR-mediated signaling and downstream IL-2 production. For the mechanisms, STAP-2 associated with TCR-proximal CD3ζ immunoreceptor tyrosine activation motifs and phosphorylated LCK, resulting in enhancement of their binding after TCR stimulation. In parallel, STAP-2 expression is required for full activation of downstream TCR signaling. Importantly, STAP-2–deficient mice exhibited slight phenotypes of CD4+ T-cell–mediated inflammatory diseases, such as experimental autoimmune encephalomyelitis, whereas STAP-2–overexpressing transgenic mice showed severe phenotypes of these diseases. Together, STAP-2 is an adaptor protein to enhance TCR signaling; therefore, manipulating STAP-2 will have an ability to improve the treatment of patients with autoimmune diseases as well as the chimeric Ag receptor T cell therapy.

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Section: Phosphorylation Of Stap-2 At Tyr250 By Lck Is Required To Re...mentioning

confidence: 99%

STAP-2 Is a Novel Positive Regulator of TCR-Proximal Signals

Saitoh

Kashiwakura

Kagohashi

et al. 2022

The Journal of Immunology

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“…STAP-2 deficiency results in the reduction of SDF-1α-induced T cell migration, whereas Jurkat cells overexpressing STAP-2 show increased cell migration toward SDF-1α [ 34 ]. Mechanical studies have suggested that STAP-2 affects the activity of Rho GTPases, such as RhoA, Rac1, and Cdc42, with its ability to function as a scaffold protein between Vav1 and Pyk2 to initiate Pyk2-mediated Vav1 phosphorylation in T cells [ 34 , 35 ]. STAP-2 Y250 phosphorylation is also an important step for the successful function of an adaptor protein between these molecular types of machinery [ 35 ].…”

Section: Functional Role Of Stap-2 In T Cellsmentioning

confidence: 99%

The Functional Properties and Physiological Roles of Signal-Transducing Adaptor Protein-2 in the Pathogenesis of Inflammatory and Immune Disorders

2022

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Adaptor molecules play a crucial role in signal transduction in immune cells. Several adaptor molecules, such as the linker for the activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76), are essential for T cell development and activation following T cell receptor (TCR) aggregation, suggesting that adaptor molecules are good therapeutic targets for T cell-mediated immune disorders, such as autoimmune diseases and allergies. Signal-transducing adaptor protein (STAP)-2 is a member of the STAP family of adaptor proteins. STAP-2 functions as a scaffold for various intracellular proteins, including BRK, signal transducer, and activator of transcription (STAT)3, STAT5, and myeloid differentiation primary response protein (MyD88). In T cells, STAP-2 is involved in stromal cell-derived factor (SDF)-1α-induced migration, integrin-dependent cell adhesion, and Fas-mediated apoptosis. We previously reported the critical function of STAP-2 in TCR-mediated T cell activation and T cell-mediated autoimmune diseases. Here, we review how STAP-2 affects the pathogenesis of T cell-mediated inflammation and immune diseases in order to develop novel STAP-2-targeting therapeutic strategies.

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“…The other possible involvement of STAP-2 in SDF-1α-mediated signals is the regulation of Pyk2, which forms signaling complexes with paxillin, the CT10 regulator of kinase (Crk), and p130 Crkassociated substrate (Cas). 32) STAP-2 directly interacts with Pyk2 and upregulates Pyk2 phosphorylation. Pyk2 itself can induce STAP-2 Tyr250 phosphorylation, which is critical for maximal interactions between STAP-2 and Pyk2 33) (Fig.…”

Section: Effects Of Stap-2 On T Cell Migrationmentioning

confidence: 99%

STAP-2 Adaptor Protein Regulates Multiple Steps of Immune and Inflammatory Responses

Matsuda

Oritani

2021

Biological & Pharmaceutical Bulletin

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Signal-transducing adaptor protein (STAP)-2 is an adaptor molecule involved in regulation of several intracellular signaling events in immune cells. STAP-2 contains a pleckstrin homology domain at the N-terminus, an src homology domain in the central portion and a proline-rich region at the C-terminus. STAP-2 also has a YXXQ motif, which is a potential signal transducer and activator of transcription (STAT)3-binding site. STAP-2 influences the STAT3 and STAT5 activity, integrin-mediated T cell adhesion, chemokineinduced T cell migration, Fas-mediated T cell apoptosis, Toll-like receptor-mediated macrophage functions, macrophage colony-stimulating factor-induced macrophage activation, and the high-affinity immunoglobulin E receptor-mediated mast cell activation. This article reviews the current understanding of roles of the STAP-2 during immune and/or inflammatory responses, and discusses possible therapeutic applications of targeting STAP-2 proteins in immune-related disorders.

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STAP-2 interacts with Pyk2 and enhances Pyk2 activity in T-cells

Cited by 14 publications

References 32 publications

STAP-2 Is a Novel Positive Regulator of TCR-Proximal Signals

STAP-2 Is a Novel Positive Regulator of TCR-Proximal Signals

The Functional Properties and Physiological Roles of Signal-Transducing Adaptor Protein-2 in the Pathogenesis of Inflammatory and Immune Disorders

STAP-2 Adaptor Protein Regulates Multiple Steps of Immune and Inflammatory Responses

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