An SH2-domain-containing kinase negatively regulates the phosphatidylinositol-3 kinase pathway

Moniakis, John; Funamoto, Satoru; Fukuzawa, Masashi; Meisenhelder, Jill; Araki, Tsuyoshi; Abe, Tomoaki; Meili, Ruedi; Hunter, Tony; Williams, Jeffrey; Firtel, Richard A.

doi:10.1101/gad.871001

Cited by 27 publications

(25 citation statements)

References 49 publications

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“…These were then electrophoresed on an SDSpolyacrylamide gel, and the proteins were visualized with Coomassie. pleckstrin homology domain on CRAC then binds to these lipids (28,76). We find that recombinant countin modulates the GTP␥S stimulated activity of adenylyl cyclase without affecting the basal or Mn 2ϩ -stimulated activities.…”

Section: Fig 5 a 1-min Treatment Of Countinmentioning

confidence: 85%

Cells Respond to and Bind Countin, a Component of a Multisubunit Cell Number Counting Factor

Gao

Ehrenman

Tang

et al. 2002

Journal of Biological Chemistry

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In Dictyostelium discoideum counting factor (CF), a secreted ϳ450-kDa complex of polypeptides, inhibits group and fruiting body size. When the gene encoding countin (a component of CF) was disrupted, cells formed large groups. We find that recombinant countin causes developing cells to form small groups, with an EC 50 of ϳ3 ng/ml, and affects cAMP signal transduction in the same manner as semipurified CF. Recombinant countin increases cell motility, decreases cell-cell adhesion, and regulates gene expression in a manner similar to the effect of CF. However, countin does not decrease adhesion or group size to the extent that semipurified CF does. A 1-min exposure of developing cells to countin causes an increase in F-actin polymerization and myosin phosphorylation and a decrease in myosin polymerization, suggesting that countin activates a rapid signal transduction pathway.125 I-Labeled countin has countin bioactivity, and binding experiments suggest that vegetative and developing cells have ϳ53 cell-surface sites that bind countin with a K D of ϳ1.5 ng/ml or 60 pM. We hypothesize that countin regulates cell development through the same pathway as CF and that other proteins within the complex may modify the activity of countin and/or have independent size-regulating activities.

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Section: Fig 5 a 1-min Treatment Of Countinmentioning

confidence: 85%

Cells Respond to and Bind Countin, a Component of a Multisubunit Cell Number Counting Factor

Gao

Ehrenman

Tang

et al. 2002

Journal of Biological Chemistry

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“…Such non-traditional tyrosine kinases may explain the expansion and maintenance of SH2 domain proteins in Amoebozoa such as Dictyostelium discoideum. It is also in Amoebozoa that we first encounter SH2 domains linked to a dual-specificity kinase, the Ser/ Thr/Tyr kinase Shk [50]. Despite the absence of PTKs, tyrosine phosphorylation has been reported in D. discoideum and can be observed in the phosphorylation of the C-terminus of STATc [51,52] (figure 2b).…”

Section: Sh2 Domains Predate Dedicated Protein-tyrosine Kinasesmentioning

confidence: 97%

Evolution of SH2 domains and phosphotyrosine signalling networks

Liu

Nash

2012

Phil. Trans. R. Soc. B

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Src homology 2 (SH2) domains mediate selective protein-protein interactions with tyrosine phosphorylated proteins, and in doing so define specificity of phosphotyrosine (pTyr) signalling networks. SH2 domains and protein-tyrosine phosphatases expand alongside protein-tyrosine kinases (PTKs) to coordinate cellular and organismal complexity in the evolution of the unikont branch of the eukaryotes. Examination of conserved families of PTKs and SH2 domain proteins provides fiduciary marks that trace the evolutionary landscape for the development of complex cellular systems in the proto-metazoan and metazoan lineages. The evolutionary provenance of conserved SH2 and PTK families reveals the mechanisms by which diversity is achieved through adaptations in tissue-specific gene transcription, altered ligand binding, insertions of linear motifs and the gain or loss of domains following gene duplication. We discuss mechanisms by which pTyr-mediated signalling networks evolve through the development of novel and expanded families of SH2 domain proteins and the elaboration of connections between pTyr-signalling proteins. These changes underlie the variety of general and specific signalling networks that give rise to tissue-specific functions and increasingly complex developmental programmes. Examination of SH2 domains from an evolutionary perspective provides insight into the process by which evolutionary expansion and modification of molecular protein interaction domain proteins permits the development of novel protein-interaction networks and accommodates adaptation of signalling networks.

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“…In addition, LO has also been found in association with fine filamentous structures in the cytoplasm of fibroblasts, a finding consistent with localization with cytoskeletal proteins (32,74). Thus, various workers have speculated that LO inhibits Ras signaling by altering or preventing either the recruitment or the association of Ras, Raf, PI3K, PDK1, and/or Akt to the inner surface of the plasma membrane, which is critical for their activation (9,30,37,45,67) or subsequent signaling steps, or by stimulating an antagonist, such as the 14-3-3 protein (42) or the plasma membrane protein SHK-1 (48), which were recently shown to inhibit the recruitment of Raf and Akt to the plasma membrane, respectively. We show here that myristylation of either Akt or PDK1, which leads to their constitutive binding to the plasma membrane, counteracts the inhibitory effects of LO, in a PI3K-independent manner.…”

Section: Discussionmentioning

confidence: 99%

Lysyl Oxidase Inhibits Ras-Mediated Transformation by Preventing Activation of NF-κB

Jeay

Pianetti

Kagan

et al. 2003

Molecular and Cellular Biology

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Lysyl oxidase (LO), which catalyzes the oxidation of lysine residues, was previously shown to have antioncogenic activity on ras-transformed cells. Since oncogenic Ras mediates transformation, in part, through the activation of the transcription factor nuclear factor-B (NF-B), we tested here the effects of LO on NF-B activity. Expression of LO in ras-transformed NIH 3T3 cells led to decreased NF-B binding and activity, as well as the expression of the NF-B target gene c-myc. Importantly, ectopic expression of LO led to a dramatic decrease in colony formation by ras-transformed NIH 3T3 cells, a finding comparable to the expression of the IB␣ dominant-negative mutant, which could be rescued by p65/p50 NF-B subunit expression. LO was unable to directly inhibit the activity of ectopically expressed p65 and c-Rel NF-B subunits, suggesting that LO affected an upstream signaling pathway(s) induced by Ras. Consistent with this hypothesis, LO expression decreased both the rate of IB␣ turnover and the activities of IKK␣ and IKK␤. Moreover, the ectopic expression of a constitutively active version of either kinase reversed the negative effects of LO. Ras can induce NF-B via both the phosphatidylinositol 3-kinase (PI3K)/Akt and Raf/MEK pathways. LO potently downregulated the PI3K and Akt kinases, while partially inhibiting MEK kinase activity. Expression of a constitutively activated, myristylated Akt or PDK1 was able to counteract the effect of LO on NF-B, whereas constitutively activated Raf was only partially effective. Importantly, LO blocked membrane localization of Akt and PDK1 in Ras-transformed cells. Overall, these results strongly argue that the anti-oncogenic effects of LO on rasmediated transformation are due to its ability to inhibit signaling pathways that lead to activation of NF-B.Lysyl oxidase (LO; protein-6-oxidase [EC 1.4.3.13]) is the key enzyme that controls collagen and elastin maturation (53,62). LO catalyzes the oxidative deamination of peptidyl lysine and hydrolysine to peptidyl-␣-aminoadipic-␦-semialdehyde in elastin and collagen chains. The consequent aldehydes lead to a spontaneous condensation forming inter-and intrachain cross-links. This posttranslational modification of extracellular matrix molecules plays a very important role in collagen and elastin structural aspects and possibly in triggering still-unknown signal transduction pathways. Several reports have suggested a clear association between organ fibrosis and increased LO activity (10,31,64). The most intriguing aspect regarding LO activity relates to its putative cell phenotype control and tumor suppressor activity. LO was identified as a "ras recision gene" (rrg), and levels of LO are decreased in cells transformed by ras or ras-dependent oncogenes (12, 34, 39). Furthermore, Friedman and coworkers showed that ras-transfected NIH 3T3 cells induced to revert by beta or gamma interferon would return to their transformed phenotype upon transfection with an antisense LO vector, and retransformation did not affect p21 ras levels (12, 34). ...

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An SH2-domain-containing kinase negatively regulates the phosphatidylinositol-3 kinase pathway

Cited by 27 publications

References 49 publications

Cells Respond to and Bind Countin, a Component of a Multisubunit Cell Number Counting Factor

Cells Respond to and Bind Countin, a Component of a Multisubunit Cell Number Counting Factor

Evolution of SH2 domains and phosphotyrosine signalling networks

Lysyl Oxidase Inhibits Ras-Mediated Transformation by Preventing Activation of NF-κB

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