Rap1 Is a Potent Activation Signal for Leukocyte Function-Associated Antigen 1 Distinct from Protein Kinase C and Phosphatidylinositol-3-OH Kinase

Katagiri, Koko; Hattori, Masao; Minato, Nagahiro; Irie, Shinkichi; Takatsu, Kiyoshi; Kinashi, Tatsuo

doi:10.1128/mcb.20.6.1956-1969.2000

Cited by 310 publications

(309 citation statements)

References 75 publications

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“…Expression of constitutively active Rap1 in thymocytes increases their basal adhesion to the b1 and b2 ligands fibronectin and ICAM-1, respectively [55]. Moreover, dominant-negative forms for Rap1 have been shown to block TCRinduced integrin activation in cell lines [56]. We have observed that Rap1 activation following TCR stimulation is blocked by the GBF in Jurkat cells (data not shown).…”

Section: Discussionmentioning

confidence: 82%

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: 82%

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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“…Several lines of evidence have supported the notion that Rap1 plays an important role in integrin-mediated leukocyte adhesion. An active form of Rap1 potently induces the activation of integrins and subsequent cell aggregation (Katagiri et al, 2000;Reedquist et al, 2000), whereas a dominant-negative form of Rap1 and GTPaseactivating proteins for Rap1 including SPA-1 inhibited cell adhesion triggered by ligation of the T-cell receptor or CD31 (Tsukamoto et al, 1999;Katagiri et al, 2000;Reedquist et al, 2000). Likewise, lipopolysaccharide-induced activation of integrins in macrophages requires Rap1 (Schmidt et al, 2001a).…”

Section: Discussionmentioning

confidence: 99%

Differential roles of Ras and Rap1 in growth factor-dependent activation of phospholipase Cε

et al. 2002

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“…Rho-family GTPases, RhoA, Rac1 and Cdc42, regulate assembly/disassembly of actin structures, focal adhesions and focal complexes (reviewed in Magnusson and Mosher, 1998;Schlaepfer and Hunter, 1998;Schoenwaelder and Burridge, 1999;Tapon and Hall, 1997). Rap1 can a ect cell adhesion and cytoskeletal responses (Katagiri et al, 2000;Kawata et al, 1988;Kitayama et al, 1989;Reedquist et al, 2000;Tsukamoto et al, 1999). Second, FN matrix assembly has been shown to be dependent on cytoskeletal rearrangements regulated by Rho-family GTPases (Christopher et al, 1997;Wu et al, 1995;Zhang et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases

2001

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Rap1 Is a Potent Activation Signal for Leukocyte Function-Associated Antigen 1 Distinct from Protein Kinase C and Phosphatidylinositol-3-OH Kinase

Cited by 310 publications

References 75 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

Differential roles of Ras and Rap1 in growth factor-dependent activation of phospholipase Cε

c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases

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