The role of Gads in hematopoietic cell signalling

Liu, Stanley K.; Berry, Donna M.; McGlade, C. Jane

doi:10.1038/sj.onc.1204771

Cited by 70 publications

(66 citation statements)

References 68 publications

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“…SH2 and SH3 domains are also the almost exclusive building blocks of a group of small adaptor proteins, which includes in addition to the Crk and CRKL proteins the Grb2 and Nck adaptor families, known to play important roles in the regulation of cell proliferation, di erentiation, immune receptor signalling etc. (Li and She, 2000;Norian and Koretzky, 2000;Li, 2001, this issue;McGlade, 2001, this issue; for domain composition of small SH2/SH3 adaptors see Feller et al, 1998). The SH2 domains of these adaptors are often the connection to the upstream partner(s) within a signalling cascade, while SH3 domains serve in many cases to couple a protein to its e ector(s).…”

Section: Protein ± Protein Interaction Domainsmentioning

confidence: 99%

Crk family adaptors–signalling complex formation and biological roles

2001

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Section: Protein ± Protein Interaction Domainsmentioning

confidence: 99%

Crk family adaptors–signalling complex formation and biological roles

2001

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“…This implies that Grap-2 is involved in signal transduction of as yet undefined (receptor) tyrosine kinases in these cells. Grap-2 and Grb2 share the same docking sites on several proteins including M-CSFR (Bourette et al, 1998;Liu et al, 2001), which raises the possibility that Grap-2 effects could be achieved at least in part through competition with Grb2. Consistent with this, addition of Grb2 in cotransfection experiments was able to revert partially the Grap-2 effect on RET-induced NF-kB activity (see supplementary material).…”

mentioning

confidence: 99%

“…In our experiments performed with the cytoplasmic tail of human RET ranging from amino acids 718-1114 we identified a novel Grb2-related adaptor protein. Owing to its simultaneous identification by several groups (reviewed in Liu et al, 2001), this adaptor has acquired different names. It is here refered to as Grap-2 in accordance with the first report of the human homologue (Qiu et al, 1998).…”

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confidence: 99%

Grap-2, a novel RET binding protein, is involved in RET mitogenic signaling

et al. 2003

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Signal transduction of the RET receptor tyrosine kinase is involved in developmental processes as well as in neoplastic transformation. Activation of RET initiates receptor autophosphorylation on specific tyrosines that act as docking sites for downstream signaling molecules. Using the cytoplasmatic part of RET as bait in a yeast two-hybrid screen, we identified a novel SH2 and SH3 domain containing adaptor protein previously termed Grap-2/Grf40/GrpL/GRID and its murine homologue as Gads/Mona, respectively. This protein, predominantly expressed in cells of hematopoietic origin, is involved in signaling downstream of the T-cell receptor and the receptor for monocyte colony-stimulating factor. Here, we show that Grap-2 is also expressed in neuroendocrine tumors and cell lines known to bear mutated forms of RET. Endogenously expressed RET and Grap-2 coimmunoprecipitate from lysates of a medullary thyroid carcinoma cell line. Grap-2 directly associates with RET in pull-down experiments using in vitro translated proteins. Overexpression of Grap-2 inhibits RET-induced NF-jB activation, and cotransfection of Grap-2 significantly reduces focus formation induced by oncogenic RET in NIH 3T3 cells. Taken together, these results suggest that besides being involved in tyrosine kinase signaling in hematopoietic cells, Grap-2 plays a tissue-specific role as an inhibitor of RET mitogenic signaling.

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Section: Introductionmentioning

confidence: 99%

“…The N-terminal SH2 domain of PLCg1 binds to LAT phospho-tyrosine 132 (pY 132 ) and this interaction recruits PLCg1 to the GEM, leading to TCR-induced tyrosine phosphorylation and enzyme activation [10][11][12]. However, LAT is unable to activate PLCg1 in the absence of SLP76, which is indirectly recruited to LAT via Gads [13,14].SLP76 consists of three domains that mediate interactions with many proteins, leading to activation of TCR-mediated signaling pathways. An N-terminal acidic domain containing three tyrosine phosphorylation sites and a central proline-rich region containing the Gads-binding sites are indispensable for PLCg1 activation [15].…”

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confidence: 99%

Competition between SLP76 and LAT for PLCγ1 binding in resting T cells

et al. 2010

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The constitutive interaction between the P1 domain (a 67-amino-acid functional domain within the proline-rich region) of SLP76 and the SH3 domain of phospholipase Cc1 (PLCc1) has been shown. To determine the significance of the interaction between SLP76 and PLCc1 in resting T cells, we examined molecules associated with PLCc1 in the absence of both SLP76 and, more specifically, the P1 domain of SLP76. Using a mutant Jurkat T-cell line, we showed that PLCc1 associated with LAT when the constitutive association with SLP76 was blocked. We also found that the PLCc1 association with LAT occurred in the membranes of resting T cells. Further experiments demonstrated that LAT competed with SLP76 for PLCc1 binding and that the LAT interaction with PLCc1 was mediated by the SH3 domain of PLCc1. Collectively, these results suggest that the constitutive association of SLP76 with PLCc1 is required to prevent the association with LAT as well as the premature recruitment of PLCc1 to the cell membrane.Key words: LAT . Phospholipase Cc1 . SSLP76 . Signalling . T cell IntroductionEngagement of the TCR triggers a complex cascade of signaling events leading to T-cell activation. A key initial event in the T-cell signaling pathway is tyrosine phosphorylation and activation of PLCg1 (phospholipase Cg1) [1,2]. TCR signaling pathways activate Src-, Syk-, and Tek-family protein tyrosine kinases that induce phosphorylation of many proteins including PLCg1 [3,4]. The adaptor proteins LAT linker for activation of T cells, SLP76 (Src homology 2-domain-containing leukocyte protein of 76 kDa), and Gads (Grb2-related adaptor downstream of Shc) appear to constitute an integrated signaling unit that couples TCR-mediated activation of cytoplasmic protein tyrosine kinases to PLCg1 enzyme activation [5,6].LAT is a transmembrane adaptor protein containing two palmitoylated cysteine residues proximal to the transmembrane domain that is constitutively localized to specialized membrane microdomains known as glycosphingolipid-enriched membrane domains (GEM), lipid rafts, or detergent-insoluble membrane domains [7,8]. LAT is heavily tyrosine-phosphorylated upon TCR stimulation, creating binding motifs for proteins containing Src homology (SH) 2 domains [8,9]. The N-terminal SH2 domain of PLCg1 binds to LAT phospho-tyrosine 132 (pY 132 ) and this interaction recruits PLCg1 to the GEM, leading to TCR-induced tyrosine phosphorylation and enzyme activation [10][11][12]. However, LAT is unable to activate PLCg1 in the absence of SLP76, which is indirectly recruited to LAT via Gads [13,14].SLP76 consists of three domains that mediate interactions with many proteins, leading to activation of TCR-mediated signaling pathways. An N-terminal acidic domain containing three tyrosine phosphorylation sites and a central proline-rich region containing the Gads-binding sites are indispensable for PLCg1 activation [15]. A functionally important 67 amino acid segment within the proline-rich region of SLP76, denoted the P1 region, binds to the SH3 domain of PLCg1 in re...

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The role of Gads in hematopoietic cell signalling

Cited by 70 publications

References 68 publications

Crk family adaptors–signalling complex formation and biological roles

Crk family adaptors–signalling complex formation and biological roles

Grap-2, a novel RET binding protein, is involved in RET mitogenic signaling

Competition between SLP76 and LAT for PLCγ1 binding in resting T cells

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