Characterization of the Tyrosine Kinase Tnk1 and Its Binding with Phospholipase C-γ1

Felschow, Donna M.; Civin, Curt I.; Hoehn, Gerard

doi:10.1006/bbrc.2000.2887

Cited by 16 publications

(21 citation statements)

References 32 publications

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“…In conclusion, TNK1 is constitutively phosphorylated/active upon expression and therefore likely to be regulated by expression. TNK1 protein is reportedly expressed in fetal blood cells and in some tumor cell lines including prostate cancer cells (Felschow et al, 2000). We found very little TNK1 expression in two prostate cancer cell lines, LnCap and PC3.…”

Section: Tnk1 Is Constitutively Active Upon Expressionmentioning

confidence: 58%

“…Messenger RNA (mRNA) expression of TNK1 is detectable in B-cell progenitors, fetal tissues, leukemia and tumor cell lines (Hoehn et al, 1996). TNK1 protein is expressed in fetal blood cells, but not in other hematopoietic tissues (Felschow et al, 2000). Our data show that expression of TNK1 is epigenetically silenced in certain tumor cells.…”

Section: Introductionmentioning

confidence: 69%

“…Our data show that expression of TNK1 is epigenetically silenced in certain tumor cells. Apart from the fact that TNK1 interacts with Phospholipase C gamma (PLC-g) (Felschow et al, 2000) little is known about the signaling pathways regulated by this tyrosine kinase.…”

Section: Introductionmentioning

confidence: 99%

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Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

et al. 2007

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Section: Tnk1 Is Constitutively Active Upon Expressionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 69%

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Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

et al. 2007

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“…2, 3). Whereas the 47-kDa Kos1 is ubiquitously expressed in mouse tissues, as well as human fetal blood and leukemia cell lines, the predicted 72-kDa Tnk1 can be detected in human fetal blood, but not in mouse cells, by Western blotting (3,33). A point mutation in Tnk1/Kos1 that inactivates the catalytic activity has been shown to abolish its growth inhibitory properties, indicating that the tyrosine kinase activity is required for Tnk1/Kos1 function (2,3).…”

Section: Discussionmentioning

confidence: 99%

Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors

Hoare

Reinhard³

et al. 2008

Cancer Research

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Tnk1/Kos1 is a non-receptor protein tyrosine kinase implicated in negatively regulating cell growth in a mechanism requiring its intrinsic catalytic activity. Tnk1/Kos1 null mice were created by homologous recombination by deleting the catalytic domain. Both Tnk1 +/À and Tnk1 À/À mice develop spontaneous tumors, including lymphomas and carcinomas, at high rates [27% (14 of 52) and 43% (12 of 28), respectively]. Tnk1/Kos1 expression is silenced in tumors that develop in Tnk1 +/À mice but not in adjacent uninvolved tissue, and silencing occurs in association with Tnk1 promoter hypermethylation. Tissues and murine embryonic fibroblasts derived from Tnk1/Kos1-null mice exhibit proportionally higher levels of basal and epidermal growth factor-stimulated Ras activation that results from increased Ras-guanine exchange factor (GEF) activity. Mechanistically, Tnk1/Kos1 can directly tyrosine phosphorylate growth factor receptor binding protein 2 (Grb2), which promotes disruption of the Grb2-Sos1 complex that mediates growth factor-induced Ras activation, providing dynamic regulation of Ras GEF activity with suppression of Ras. Thus, Tnk1/Kos1 is a tumor suppressor that functions to down-regulate Ras activity.

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“…Consistent with this analysis, direct binding of PLCγ1-SH3 to peptides from TNK1 and dynamin representing putative recognition sites has been demonstrated. 20,37 Other XPXXPXR sequences in c-Cbl and SOS1 (group B), while lacking proline at the position following the compass arginine, may nevertheless exhibit significant affinity for PLCγ1-SH3, since elimination of the corresponding proline in SLP-76 did not abolish binding (Table 1). Although both CAIR-1/BAG-3 and SAM 68 interact with PLCγ1-SH3, 19,38 neither contains a class II motif (group C), suggesting that PLCγ1-SH3 may also recognize other motifs, as recently demonstrated for Gads-SH3.…”

Section: Interaction Of Plcγ1-sh3 With Other Signaling Proteinsmentioning

confidence: 99%

Structural Basis for Recognition of the T Cell Adaptor Protein SLP-76 by the SH3 Domain of Phospholipase Cγ1

Deng

Velikovsky

Swaminathan

et al. 2005

Journal of Molecular Biology

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The enzyme phospholipase Cγ1 (PLCγ1) is essential for Tcell signaling and activation. Following T cell receptor ligation, PLCγ1 interacts through its SH2 and SH3 domains with the adaptors LAT and SLP-76, respectively, to form a multiprotein signaling complex that leads to activation of PLCγ1 by Syk tyrosine kinases. To identify the binding site for PLCγ1 in SLP-76, we used isothermal titration calorimetry to measure affinities for the interaction of PLCγ1-SH3 with a set of overlapping peptides spanning the central proline-rich region of SLP-76. PLCγ1-SH3 bound with high specificity to the SLP-76 motif 186 PPVPPQRP 193 , which represents the minimal binding site. To understand the basis for selective recognition, we determined the crystal structures of PLCγ1-SH3 in free form, and bound to a 10-mer peptide containing this site, to resolutions of 1.60 Å and 1.81 Å, respectively. The structures reveal that several key contacting residues of the SH3 shift toward the SLP-76 peptide upon complex formation, optimizing the fit and strengthening hydrophobic interactions. Selectivity results mainly from strict shape complementarity between protein and peptide, rather than sequencespecific hydrogen bonding. In addition, Pro193 of SLP-76 assists in positioning Arg192 into the compass pocket of PLCγ1-SH3, which coordinates the compass residue through an unusual aspartate. The PLCγ1-SH3/SLP-76 structure provides insights into ligand binding by SH3 domains related to PLCγ1-SH3, as well as into recognition by PLCγ1 of signaling partners other than SLP-76. Keywords crystal structure; SH3; calorimetry; T cell signaling; phospholipase Cγ1The enzyme phospholipase Cγ1 (PLCγ1) is an essential signal transducing element in T cell activation and development. 1,2 This multidomain protein comprises two Src homology 2 (SH2), one Src homology 3 (SH3), one pleckstrin homology (PH), and two catalytic domains (lipase and C2). 3 PLCγ1 interacts with tyrosine-phosphorylated sites on target proteins through its SH2 domains, and with proline-rich sequences through its SH3, resulting in formation of specific complexes that mediate T cell signaling. 1,2,4 In addition, PLCγ1 plays a pivotal role in cellular growth and proliferation through interactions with various growth factor receptors, such as epidermal growth factor receptor, 3,[5][6][7] and has been shown to function as a guanine nucleotide exchange factor for the nuclear GTPase PIKE. 8 Following engagement of the T cell receptor (TCR) by MHC/peptide ligands, the transmembrane adaptor protein, linker for activation of T cells (LAT) SLP-76 is composed of three distinct domains: (1) an N-terminal domain bearing tyrosine residues that become phosphorylated following TCR engagement, enabling SLP-76 to bind the SH2-containing proteins Vav and Nck; (2) a C-terminal SH2 domain which binds phosphorylated ADAP; and (3) a central proline-rich region that contains binding sites for the SH3 domains of Gads and PLCγ1. 1,2 The binding site for Gads-SH3 has been precisely mapped to residues 233−241 o...

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Characterization of the Tyrosine Kinase Tnk1 and Its Binding with Phospholipase C-γ1

Cited by 16 publications

References 32 publications

Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

Tnk1/Kos1 Knockout Mice Develop Spontaneous Tumors

Structural Basis for Recognition of the T Cell Adaptor Protein SLP-76 by the SH3 Domain of Phospholipase Cγ1

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