Coupling of the TCR to Integrin Activation by SLAP-130/Fyb

Peterson, Erik; Woods, Melody L.; Dmowski, Sally A.; Derimanov, Geo; Jordan, Martha S.; Wu, Jiansheng; Myung, Peggy; Liu, Qinghua; Pribila, Jonathan T.; Freedman, Bruce D.; Shimizu, Yoji; Koretzky, Gary A.

doi:10.1126/science.1063486

Cited by 298 publications

(365 citation statements)

References 25 publications

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“…Furthermore, agonists that directly stimulate integrin activity were able to induce increased adhesion, suggesting that hematopoietic cells from this patient express structurally intact integrins. A constitutively enhanced clustering of the LFA-1 integrin on T cells from this patient was also noted and is particularly interesting in light of in vitro studies suggesting a critical role for LFA-1 clustering in T cell receptor-mediated activation of LFA-1 (6,7,11,12).…”

supporting

confidence: 53%

Disabling multiple integrins from the inside out

Shimizu¹

2003

J. Clin. Invest.

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supporting

confidence: 53%

Disabling multiple integrins from the inside out

Shimizu¹

2003

J. Clin. Invest.

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“…However, the Cri1 candidate interval can also be considered to contain genes with a known function in the innate immune system such as the complement component 9 (C9; 6.4 Mb) or the scavenger receptor Enpp2 (54.7 Mb). It also overlaps the FYNbinding protein (Fyb; 6.5 Mb) for which deficient mice display reduced T-cell proliferation 27 as well as the interleukin 7 receptor (Il7r; 9.4 Mb), known to be an important regulator of B-and T-cell proliferation/ differentiation. 28 Although the Il7r gene seems relatively far proximal of the peak linkage region of the Cri1 locus, it is an intriguing candidate as B-cell function has been found to be essential for C. rodentium infection survival.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of Cri1, a locus controlling mortality during Citrobacter rodentium infection in mice

Diez

Zhu

et al. 2011

Genes Immun

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Infection of inbred mouse strains with Citrobacter rodentium represents an ideal model to reveal the genetic factors controlling host resistance to noninvasive enteric bacterial pathogens. We have chosen a positional cloning approach to identify putative gene(s) that control the known difference in survival between resistant C57BL/6J and susceptible C3H/HeJ and C3H/HeOuJ mice. Our work has identified one major locus within proximal chromosome 15 that is responsible for the marked susceptibility of both C3H strains, and we formally exclude Tlr4 from control of survival to this pathogen. We have named this new host resistance locus Cri1 (Citrobacter rodentium infection 1). The Cri1 genetic interval currently spans B16 Mb and it confers survival to the infection in a recessive manner. Transfer of the Cri1 locus from the surviving B6 mice into a congenic mouse with a C3Ou genetic background confirms its overall chromosomal localization and its highly significant effect on host survival. The C3Ou.B6-Cri1 mice thus produced have also enabled us to dissociate the control of mouse survival from the control of bacterial load early in the infection as well as from control of colonic hyperplasia.

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“…To date, a role for SLP-76 in integrin activation has been limited to its association with ADAP, inasmuch as prevention of SLP-76/ADAP binding inhibits conjugate formation, which has been shown to be an integrin-mediated event [33]. ADAP itself has been directly linked to integrin activation, as ADAP -/-T cells do not adhere to fibronectin, ICAM, or VCAM following TCR ligation [31,32]. One model for how a SLP-76/ ADAP association may lead to integrin activation is through Src kinase-associated phosphoprotein of 55 kDa, an adaptor that is constitutively associated with ADAP [52] and has been linked to TCR-induced integrin activation [53,54].…”

Section: Discussionmentioning

confidence: 99%

“…Its exact role and the molecular mechanism for SLP-76-dependent integrin activation, however, are unclear. Recent data have shown that ADAP, a protein known to be involved in integrin activation [31,32], requires association with SLP-76 via the SLP-76 SH2 domain to mediate enhanced integrin-dependent T cell/ APC conjugate formation and adhesion to ICAM-1 (a b2 ligand) upon overexpression in Jurkat cells [31]. Complementing this finding, overexpression of the SH2 domain of SLP-76 blocks conjugate formation [33].…”

Section: Introductionmentioning

confidence: 90%

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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Coupling of the TCR to Integrin Activation by SLAP-130/Fyb

Cited by 298 publications

References 25 publications

Disabling multiple integrins from the inside out

Disabling multiple integrins from the inside out

Identification and characterization of Cri1, a locus controlling mortality during Citrobacter rodentium infection in mice

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

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