Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein

Gout, Ivan; Middleton, Gayle; Adu, Jimi; Ninkina, Natalia; Дробот, Л. Б.; Filonenko, Valeriy; Matsuka, Gennady; Davies, Alun M.; Waterfield, Michael D.; Buchman, Vladimir L.

doi:10.1093/emboj/19.15.4015

Cited by 132 publications

(160 citation statements)

References 78 publications

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“…It should be noted that while numerous adapter-like proteins are known to associate with the PI3K holoenzyme to activate its function, to our knowledge only two proteins have been identified that suppress PI3K activity: our protein PIK3IP1 and the negative regulator Ruk [17]. Unlike Ruk which binds to the SH3 domain of p85 alpha to reduce PI3K activity [17], PIK3IP1 is unique in that it binds directly to p110 to down modulate PI3K.…”

Section: Pik3ip1 Overexpression Augments Staurosporine Induced Apoptosismentioning

confidence: 99%

PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein

Zhu¹,

He²,

Johnson³

et al. 2007

Biochemical and Biophysical Research Communications

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Signaling initiated by Class Ia phosphatidylinositol-3-kinases (PI3Ks) is essential for cell proliferation and survival. We discovered a novel protein we call PI3K Interacting Protein 1 (PIK3IP1) that shares homology with the p85 regulatory PI3K subunit. Using a variety of in vitro and cell based assays, we demonstrate that PIK3IP1 directly binds to the p110 catalytic subunit and modulates PI3K activity. Our studies suggest that PIK3IP1 is a new type of PI3K regulator.

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Section: Pik3ip1 Overexpression Augments Staurosporine Induced Apoptosismentioning

confidence: 99%

PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein

Zhu¹,

He²,

Johnson³

et al. 2007

Biochemical and Biophysical Research Communications

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“…We have recently identified a novel adaptor-type protein named Ruk [11]. It has been cloned by other groups and named Cin85 or SETA [12,13].…”

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confidence: 99%

“…Although the precise role of this Ruk/CD2AP family is still unknown, they are involved in the control of apoptosis and the regulation of cytoskeletal architecture [11,13,[15][16][17][18].…”

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confidence: 99%

Ruk is ubiquitinated but not degraded by the proteasome

Verdier

Valovka

Zhyvoloup

et al. 2002

European Journal of Biochemistry

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The regulator of ubiquitous kinase (Ruk) protein, also known as CIN85 or SETA, is an adaptor‐type protein belonging to the CD2AP/CMS family. It was found in complexes with many signaling proteins, including phosphoinositol (PtdIns) 3‐kinase (EC 2.7.1.137), Cbl, GRB2, p130Cas and Crk. Functional analysis of these interactions, implicated Ruk in the regulation of apoptosis, receptor endocytosis and cytoskeletal rearrangements. We have recently demonstrated that overexpression of Ruk induces apoptotic death in neurons, which could be reversed by activated forms of PtdIns 3‐kinase and PKB/Akt. Furthermore, Ruk was shown to be a negative regulator of PtdIns 3‐kinase activity through binding to its P85 regulatory subunit [Gout, I., Middleton, G., Adu, J., Ninkina, N. N., Drobot, L. B., Filonenko, V., Matsuka, G., Davies, A.M., Waterfield, M. & Buchman, V. L. (2000) Embo J.19, 4015–4025]. Here, we report for the first time, that all three isoforms of Ruk (L, M and S) are ubiquitinated. Specific interaction between the E3 ubiquitin ligase Cbl and all three Ruk isoforms was demonstrated by coexpression studies in Hek293 cells. The interaction of Ruk M and S isoforms with Cbl was found to be mediated via heterodimerization with Ruk L. The use of proteosomal and lysosomal inhibitors clearly indicated that ubiquitination of Ruk L does not lead to its degradation. Based on this study, we propose a possible mechanism for the regulation of Ruk function by ubiquitination.

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“…Ruk/CIN85 plays a role in various biological processes including control of receptor tyrosine kinase signalling [1,9,18,27,28,32], rearrangement of actin cytoskeleton [30], neuronal and T cell apoptosis [5,15,26], herpes simplex virus 1 infection [21], adhesion [30] and invasion [25]. Overexpression of Ruk l /CIN85 full-length form induces apoptotic cell death of primary neurons in culture [2,15].…”

Section: Introductionmentioning

confidence: 99%

“…Overexpression of Ruk l /CIN85 full-length form induces apoptotic cell death of primary neurons in culture [2,15]. However, shorter molecular forms of Ruk/CIN85 block the pro-apoptotic effect of Ruk l /CIN85, suggesting that expression of different combinations of Ruk/CIN85 proteins in cells could be involved in the regulation of their survival and other intracellular processes [2,15]. CD2AP/CMS is required for rapid activation of PI3K and ERK/MAPK pathways by TGF-β [29].…”

Section: Introductionmentioning

confidence: 99%

Comparative study of expression of adaptor proteins Ruk/CIN85 and CD2AP/CMS in normal andtumor human uterus tissues

et al. 2009

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Adaptor proteins play an important role in facilitating protein-protein interactions and subsequent formation of signalling networks. These proteins recruit binding partners to a specific location inside the cell, and also regulate their activity. Adaptor protein Ruk/CIN85 and its structural and functional homologue CD2AP/CMS are important components of different regulatory pathways involved in control of cell proliferation, adhesion, invasion and survival, and, thus, can play a role in uterine carcinogenesis. In this work, we set out a comparative study of expression of Ruk/CIN85 and CD2AP/CMS at the level of mRNA and protein in intact uterine tissues, as well as in benign and malignant uterine tumors of different histological types. In most cases, an increase of expression levels of Ruk/CIN85 full-length form mRNA and protein, as well as CD2AP/CMS protein, were observed in uterine tumors, comparing with surrounding normal uterine tissues. Characteristic feature of conditionally normal uterine tissues, as well as benign uterine lesions, was an elevated content of high-molecular mass Ruk/CIN85 forms of 140 and 130 kDa, while an increased expression level of low-molecular mass 40 and 30 kDa Ruk/CIN85 forms was observed in the malignant tissue samples. Our findings suggest that an abnormal expression patterns of adaptor proteins Ruk/CIN85 and CD2AP/CMS in uterine tumors, and, thus, the corresponding changes in the activity of downstream signalling pathways, might be involved in maintenance of the malignant phenotype.Key words: tumorigenesis, adaptor proteins, Ruk/CIN85, CD2AP/CMS, benign and malignant uterine tumors.Abbreviations: Ruk/CIN85, regulator of ubiquitous kinase/Cbl-interacting protein of 85 kDa; CD2AP/CMS, CD2 associated protein/Cas ligand with multiple SH3 domains; Biol. Stud. 2009: 3(3); 5-16 •

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Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein

Cited by 132 publications

References 78 publications

PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein

PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein

Ruk is ubiquitinated but not degraded by the proteasome

Comparative study of expression of adaptor proteins Ruk/CIN85 and CD2AP/CMS in normal andtumor human uterus tissues

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