A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT

Ku, Gregory; Yablonski, Deborah; Manser, Edward; Lim, Louis; Weiss, Arthur

doi:10.1093/emboj/20.3.457

Cited by 99 publications

(87 citation statements)

References 51 publications

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“…However, this defect is not restored by re-expression of WT SLP-76. Similarly, re-expression of SLP-76 in J14 cells was unable to restore full TCR-induced activation of Rac1 [57]. These data show that while SLP-76 can restore most TCR-mediated signaling events in J14 cells, J14 cells may lack an additional protein(s) important for integrin adhesion.…”

Section: Discussionmentioning

confidence: 79%

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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Section: Discussionmentioning

confidence: 79%

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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“…Although this could be attributable to incomplete effects of the dominant negative mutant, it could also point to Vav-independent actin regulatory pathways. For example, Ku et al (72) have defined a p21-activated kinase activation pathway that operates independently of the SLP-76/Nck complex defined here.…”

Section: Discussionmentioning

confidence: 99%

SLP-76 Coordinates Nck-Dependent Wiskott-Aldrich Syndrome Protein Recruitment with Vav-1/Cdc42-Dependent Wiskott-Aldrich Syndrome Protein Activation at the T Cell-APC Contact Site

Zeng

Cannon

Abraham

et al. 2003

The Journal of Immunology

156

148

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We have shown previously that Wiskott-Aldrich syndrome protein (WASP) activation at the site of T cell-APC interaction is a two-step process, with recruitment dependent on the proline-rich domain and activation dependent on binding of Cdc42-GTP to the GTPase binding domain. Here, we show that WASP recruitment occurs through binding to the C-terminal Src homology 3 domain of Nck. In contrast, WASP activation requires Vav-1. In Vav-1-deficient T cells, WASP recruitment proceeds normally, but localized activation of Cdc42 and WASP is disrupted. The recruitment and activation of WASP are coordinated by tyrosine-phosphorylated Src homology 2 domain-containing leukocyte protein of 76 kDa, which functions as a scaffold, bringing Nck and WASP into proximity with Vav-1 and Cdc42-GTP. Taken together, these findings reconstruct the signaling pathway leading from TCR ligation to localized WASP activation.

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“…This raises the fascinating possibility that TCRinduced, LAT-independent signaling mechanisms (in a lymphopenic context) can lead to lymphoproliferative disease. It will be interesting to compare the LAT-independent signaling mechanisms from this situation with LAT-independent signaling described in T-cell clones (Chau and Madrenas 1999) and in Jurkat T cells (Ku et al 2001;Shan et al 2001). …”

Section: Signaling Through Latmentioning

confidence: 99%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

152

184

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The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

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A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT

Cited by 99 publications

References 51 publications

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

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

SLP-76 Coordinates Nck-Dependent Wiskott-Aldrich Syndrome Protein Recruitment with Vav-1/Cdc42-Dependent Wiskott-Aldrich Syndrome Protein Activation at the T Cell-APC Contact Site

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

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