Distinct Role of ZAP-70 and Src Homology 2 Domain-Containing Leukocyte Protein of 76 kDa in the Prolonged Activation of Extracellular Signal-Regulated Protein Kinase by the Stromal Cell-Derived Factor-1α/CXCL12 Chemokine

Kremer, Kimberly N.; Humphreys, Troy D.; Kumar, Ashok; Qian, Nan Xin; Hedin, Karen E.

doi:10.4049/jimmunol.171.1.360

Cited by 64 publications

(75 citation statements)

References 48 publications

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“…SDF-1 can guide the movement of immune cells in vivo, and it can induce tight adhesion of rolling cells to activated endothelial cells, followed by their subsequent transendothelial migration. SDF-1 also enhances T cell responses to Ag stimulation via the secretion of cytokines and the promotion of cell survival (31,32). In the present study, we have found that an adaptor molecule, STAP-2, is a novel regulator of SDF-1␣-induced chemotaxis of T cells.…”

Section: Discussionmentioning

confidence: 53%

Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1α-Induced Chemotaxis in T Cells

Sekine

Ikeda

Tsuji

et al. 2009

The Journal of Immunology

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Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2-like domains, as well as a YXXQ motif in its C-terminal region. Our previous studies revealed that STAP-2 regulates integrin-mediated T cell adhesion. In the present study, we find that STAP-2 expression affects Jurkat T cell migration after stromal cell-derived factor-1α (SDF-1α)-treatment. Furthermore, STAP-2-deficient T cells exhibit reduced cell migration after SDF-1α-treatment. Importantly, overexpression of STAP-2 in Jurkat T cells induces activation of small guanine triphosphatases, such as Rac1 and Cdc42. Regarding the mechanism for this effect, we found that STAP-2 associates with Vav1, the guanine-nucleotide exchanging factor for Rac1, and enhances downstream Vav1/Rac1 signaling. These results reveal a novel STAP-2-mediated mechanism for the regulation of SDF-1α-induced chemotaxis of T cells via activation of Vav1/Rac1 signaling.

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Section: Discussionmentioning

confidence: 53%

Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1α-Induced Chemotaxis in T Cells

Sekine

Ikeda

Tsuji

et al. 2009

The Journal of Immunology

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“…In addition to signaling downstream of the TCR, SLP-76 has been implicated in chemokine signaling in the Jurkat model system [36]. In this study, SLP-76 was found to be phosphorylated downstream of stromal cell-derived factor (SDF)-1a and to be required for Ca 2+ flux and prolongation of ERK phosphorylation in response to SDF-1a stimulation.…”

Section: Introductionmentioning

confidence: 69%

“…In Jurkat T cells, SLP-76 is required for prolonged ERK phosphorylation and for Ca 2+ flux following SDF-1 stimulation [36]. However, the SLP-76/Gads interaction is dispensable for SDF-1-induced ERK phosphorylation [36].…”

Section: Introductionmentioning

confidence: 99%

“…Although the T cell kinase Zap-70, a proximal protein tyrosine kinase required for TCR signaling, is necessary for TCR-induced integrin activation in Jurkat cells, overexpression of SLP-76 or LAT, known targets of Zap-70, fails to enhance adhesion to the b1 ligand fibronectin [34]. Furthermore, adhesion to VCAM-1 (also a b1 ligand) under shear force was found to be normal in SLP-76-deficient Jurkat cells [35].In addition to signaling downstream of the TCR, SLP-76 has been implicated in chemokine signaling in the Jurkat model system [36]. In this study, SLP-76 was found to be phosphorylated downstream of stromal cell-derived factor (SDF)-1a and to be required for Ca 2+ flux and prolongation of ERK phosphorylation in response to SDF-1a stimulation.…”

mentioning

confidence: 99%

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In vivo disruption of T cell development by expression of a dominant‐negative polypeptide designed to abolish the SLP‐76/Gads interaction

Jordan¹,

Kliche²,

Shabason³

et al. 2007

Eur J Immunol

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Multi-molecular complexes nucleated by adaptor proteins play a central role in signal transduction. In T cells, one central axis consists of the assembly of several signaling proteins linked together by the adaptors linker of activated T cells (LAT), Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), and Grb2-related adaptor downstream of Shc (Gads). Each of these adaptors has been shown to be important for normal T cell development, and their proper sub-cellular localization is critical for optimal function in cell lines. We previously demonstrated in Jurkat T cells and a rat basophilic leukemic cell line that expression of a 50-amino acid polypeptide identical to the site on SLP-76 that binds to Gads blocks proper localization of SLP-76 and SLP-76-dependent signaling events. Here we extend these studies to investigate the ability of this polypeptide to inhibit TCR-induced integrin activity in Jurkat cells and to inhibit in vivo thymocyte development and primary T cell function. These data provide evidence for the in vivo function of a dominant-negative peptide based upon the biology of SLP-76 action and suggest the possibility of therapeutic potential of targeting the SLP-76/Gads interaction. IntroductionStimulation of T cells through the T cell receptor (TCR) leads to recruitment and localization of several critical signaling proteins, which results in the generation of a macro-molecular signaling complex. Key components of this complex, or signalosome, include the adaptors Src homology 2 (SH2) domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), and Grb2-related adaptor downstream of Shc (Gads), which serves to link SLP-76 and its associated molecules to the transmembrane adaptor linker of activated T cells (LAT) [1].As an adaptor protein, SLP-76 possesses no enzymatic activity but functions via interaction with multiple proteins by way of three structural domains [2][3][4]. The N terminus harbors three tyrosines that become phos- phorylated upon TCR engagement [5,6] and have been reported to serve as docking sites for the guanine nucleotide exchange factor Vav, the adaptor protein Nck, the Tec family kinase Itk, and the p85 subunit of PI3K [7][8][9][10][11][12][13][14][15][16]. A single SH2 domain resides in the C-terminal portion of SLP-76 and links it to the adhesion and degranulation-promoting adaptor protein (ADAP) and to the hematopoietic progenitor kinase 1 [17][18][19]. Hematopoietic progenitor kinase 1, in turn, has been shown to phosphorylate SLP-76, creating a binding site for 14-3-3, a negative regulator of TCR signaling [20,21]. The central proline-rich region binds phospholipase Cc- Targeted deletion of SLP-76 in mice results in an inability of thymocytes to progress past the CD4 -CD8 -double-negative (DN) stage of development and thus a complete absence of mature T cells [28,29]. Since T cells do not develop in the absence of SLP-76, much of our knowledge of the role of SLP-76 in mature TCR signaling has been derived from the study of J14 ...

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“…86,89 CXCR4 signaling also involves the Ras-activated signaling pathway, several src-related kinases such as Src, Lyn, Fyn and Lck, T-cell activating molecule ZAP-70 and vav. 90 Recent evidence from other [91][92][93] and our 70 laboratories indicates the role of small GTPases in CXCR4 signaling. Activation of these GTPases is crucial for cell migration to an SDF-1 gradient.…”

Section: Biological Effects Of the Sdf-1-cxcr4 Axismentioning

confidence: 99%

The pleiotropic effects of the SDF-1–CXCR4 axis in organogenesis, regeneration and tumorigenesis

et al. 2006

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Proper response of normal stem cells (NSC) to motomorphogens and chemoattractants plays a pivotal role in organ development and renewal/regeneration of damaged tissues. Similar chemoattractants may also regulate metastasis of cancer stem cells (CSC). Growing experimental evidence indicates that both NSC and CSC express G-protein-coupled seven-transmembrane span receptor CXCR4 and respond to its specific ligand a-chemokine stromal derived factor-1 (SDF-1), which is expressed by stroma cells from different tissues. In addition, a population of very small embryonic-like (VSEL) stem cells that express CXCR4 and respond robustly to an SDF-1 gradient was recently identified in adult tissues. VSELs express several markers of embryonic and primordial germ cells. It is proposed that these cells are deposited early in the development as a dormant pool of embryonic/pluripotent NSC. Expression of both CXCR4 and SDF-1 is upregulated in response to tissue hypoxia and damage signal attracting circulating NSC and CSC. Thus, pharmacological modulation of the SDF-1-CXCR4 axis may lead to the development of new therapeutic strategies to enhance mobilization of CXCR4 þ NSC and their homing to damaged organs as well as inhibition of the metastasis of CXCR4 þ cancer cells.

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Distinct Role of ZAP-70 and Src Homology 2 Domain-Containing Leukocyte Protein of 76 kDa in the Prolonged Activation of Extracellular Signal-Regulated Protein Kinase by the Stromal Cell-Derived Factor-1α/CXCL12 Chemokine

Cited by 64 publications

References 48 publications

Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1α-Induced Chemotaxis in T Cells

Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1α-Induced Chemotaxis in T Cells

In vivo disruption of T cell development by expression of a dominant‐negative polypeptide designed to abolish the SLP‐76/Gads interaction

The pleiotropic effects of the SDF-1–CXCR4 axis in organogenesis, regeneration and tumorigenesis

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