Association of the tyrosine kinase LCK with phospholipase C-gamma 1 after stimulation of the T cell antigen receptor.

Weber, John R.; Bell, Gregory; Han, Mi-Young; Pawson, Tony; Imboden, John B.

doi:10.1084/jem.176.2.373

Cited by 123 publications

(38 citation statements)

References 32 publications

(57 reference statements)

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“…These observations raise the possibility that Src or some other PDGF-activated tyrosine kinase contributes to phosphorylation of PLC␥ in a PDGF-stimulated cell. This possibility is also supported by the observation that PLC␥ complexes with Src family members (52,78). Importantly, GAP has also been shown to associate with tyrosine kinases, which include members of the Src family (5,9,24,57).…”

Section: Discussionsupporting

confidence: 61%

The GTPase-Activating Protein of Ras Suppresses Platelet-Derived Growth Factor β Receptor Signaling by Silencing Phospholipase C-γ1

Valius

Secrist

Kazlauskas

1995

Molecular and Cellular Biology

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, and several other proteins. Our previous studies indicated that PI3K and PLC␥ were required for relay of the mitogenic signal of ␤PDGFR, whereas GAP and Syp did not appear to be required for this response. In this study, we further investigated the role of GAP and Syp in mitogenic signaling by ␤PDGFR. Focusing on the PLC␥-dependent branch of ␤PDGFR signaling, we constructed a series of mutant ␤PDGFRs that contained the binding sites for pairs of the receptor-associated proteins: PLC␥ and PI3K, PLC␥ and GAP, or PLC␥ and Syp. Characterization of these mutants showed that while all receptors were catalytically active and bound similar amounts of PLC␥, they differed dramatically in their ability to initiate DNA synthesis. This signaling deficiency related to an inability to efficiently tyrosine phosphorylate and activate PLC␥. Surprisingly, the crippled receptor was the one that recruited PLC␥ and GAP. Thus, GAP functions to suppress signal relay by the ␤PDGFR, and it does so by silencing PLC␥. These findings demonstrate that the biological response to PDGF depends not only on the ability of the ␤PDGFR to recruit signal relay enzymes but also on the blend of these receptor-associated proteins.For the ␤ receptor of the platelet-derived growth factor (␤PDGFR), ligand binding activates its intrinsic kinase activity and leads to phosphorylation at multiple tyrosine residues. The phosphorylated receptor associates with a set of SH2 domaincontaining proteins that includes phospholipase C-␥1 (PLC␥), the GTPase-activating protein of Ras (GAP), the regulatory subunit of phosphatidylinositol 3 kinase (PI3K), the phosphotyrosine phosphatase Syp (also called SH-PTP2, PTP-1D, SH-PTP3, PTP2C, and PTP-SH2␤), three members of the Src family (Src, Yes, and Fyn), Nck, Shc, Grb2, and several as yet unidentified proteins (1,30,82). These proteins associate with the phosphorylated receptor by a variety of mechanisms. Some proteins have specific binding sites on the receptor and associate only when the receptor is phosphorylated at these sites. For instance, binding of PLC␥, GAP, Syp, and PI3K requires phosphorylation of the receptor at tyrosines 1021, 771, 1009, and 740/751, respectively (30). Proteins such as Shc do not have a strict phosphorylation site requirement (82), and their binding to the ␤PDGFR is reminiscent of how SH2-domain containing proteins associate with the epidermal growth factor receptor (68). Grb2 appears to associate with the receptor via multiple mechanisms, either by binding to Syp, which then complexes with the phosphorylated receptor (41), or by binding directly to the receptor in response to phosphorylation of tyrosine 716 (1).At least some of the receptor-associated proteins are key players in intracellular signal transduction cascades. For instance, PLC␥ is a phosphatidylinositol-specific phosphodiesterase that is activated by tyrosine phosphorylation in response to engagement of a wide variety of cell surface receptors (reviewed in reference 60). The possibility that PLC␥ plays a direct role in mitogenic ...

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Section: Discussionsupporting

confidence: 61%

The GTPase-Activating Protein of Ras Suppresses Platelet-Derived Growth Factor β Receptor Signaling by Silencing Phospholipase C-γ1

Valius

Secrist

Kazlauskas

1995

Molecular and Cellular Biology

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“…At least in T-cell lines, a relatively large fraction of p561ck molecules are not phosphorylated at Tyr-505, and acute changes in this phosphorylation have not been observed during T-cell activation. Instead, the phosphotyrosine (PTyr) content of p561ck increases after T-cell activation (54). This suggests that p56 1k is recruited and/or activated by some other mechanism.…”

mentioning

confidence: 94%

Activation of p56lck by p72syk through physical association and N-terminal tyrosine phosphorylation.

Couture¹,

Baier²,

Oetken³

et al. 1994

Mol. Cell. Biol.

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The p56ik and p590M protein tyrosine kinases are important signal transmission elements in the activation of mature T lymphocytes by ligands to the T-cell antigen receptor (TCR)/CD3 complex. The lack of either kinase results in deficient early signaling events, and phairmacological agents that block tyrosine phosphorylation prevent T-cell activation altogether. After triggering of the TCRICD3 complex, both kinases are moderately activated and begin to phosphorylate cellular substrates, but the molecular mechanisms responsible for these changes have remained unclear. We recently found that the p72syk protein tyrosine kinase is physically associated with the TCR/CD3 complex and is rapidly tyrosine phosphorylated and activated by receptor triggering also in T cells lacking p56kk. Here we examine the regulation of p72yk and its interaction with p56"k in transfected COS-1 cells. p72'k was catalytically active and heavily phosphorylated on its putative autophosphorylation site, Tyr-518/519. Mutation of these residues to phenylalanines abolished its activity in vitro and toward cellular substrates in vivo and reduced its tyrosine phosphorylation in intact cells by -90%.Coexpression of Ick did not alter the catalytic activity of p72syk, but the expressed p56"k was much more active in the presence of p72yk than when expressed alone. This activation was also seen as increased phosphorylation of cellular proteins. Concomitantly, p56kk was phosphorylated at Tyr-192 in its SH2 domain, and a Phe-192 mutant p56kk was no longer phosphorylated by p72A"k. Phosphate was also detected in p56"k at in lymphoid cells. These findings suggest that p56kk is positively regulated by the p723* kinase.T-cell activation by ligands to the T-cell antigen receptor (TCR)/CD3 complex depends on the rapid ligand-induced tyrosine phosphorylation of cellular substrates, such as phospholipase C-yl, the t chain of the TCR, phosphatidylinositol 3-kinase, and the guanine nucleotide exchange factor p95vav (reviewed in reference 27). Inhibition of protein tyrosine kinases (PTKs) by pharmacological agents prior to TCR/CD3 stimulation blocks T-cell activation (19, 31), and overexpression of some PTKs (especially Src-related PTKs) in T cells renders them hypersensitive to TCR/CD3 stimulation (1, 10).Two members of the Src family of nonreceptor PTKs, p56ck and p59fy', which associate with the CD4/CD8 coreceptors and the TCR/CD3, respectively, are crucial in T-cell maturation (26) (2,25). In vivo, the phosphorylation of Tyr-505 is probably mediated by p5Ocsk, a PTK known to phosphorylate Src family PTKs at their conserved C-terminal regulatory site in vitro (7,33,37

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“…PLC-g1 is a multidomain enzyme that includes a pleckstrin homology (PH) domain that can bind membrane phosphoinositides, two phosphotyrosine-binding SH2 (src homology 2) domains and an SH3 (src homology 3) domain, which binds specific proline-rich sequences. PLC-g1 binding to LATwas observed even before LATwas cloned and was shown to be dependent on the amino-terminal SH2 domain of PLC-g1 (Gilliland et al 1992;Weber et al 1992;Stoica et al 1998;Irvin et al 2000). Interaction with LAT was shown to be required for both PLC-g1 activation and localization near its substrate PIP 2 at the plasma membrane (Zhang et al 1999a;Zhang et al 2000;Lin and Weiss 2001).…”

Section: Plc-g1 Binds Y132 Of Lat and Mediates Transcriptional Activamentioning

confidence: 99%

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

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

153

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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Association of the tyrosine kinase LCK with phospholipase C-gamma 1 after stimulation of the T cell antigen receptor.

Cited by 123 publications

References 32 publications

The GTPase-Activating Protein of Ras Suppresses Platelet-Derived Growth Factor β Receptor Signaling by Silencing Phospholipase C-γ1

The GTPase-Activating Protein of Ras Suppresses Platelet-Derived Growth Factor β Receptor Signaling by Silencing Phospholipase C-γ1

Activation of p56lck by p72syk through physical association and N-terminal tyrosine phosphorylation.

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

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