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

Zhu, Zhenqi; He, Xin; Johnson, Carla J.; Stoops, John; Eaker, Amanda E.; Stoffer, David S.; Bell, Aaron; Zarnegar, Reza; DeFrances, Marie C.

doi:10.1016/j.bbrc.2007.04.096

Cited by 71 publications

(105 citation statements)

References 18 publications

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“…PIK3IP1 is a relatively recently identified PI3K regulating protein. PIK3IP1 binds directly to PI3K and negatively regulates its activity (Zhu et al, 2007). PI3K pathway activation is seen in many types of cancers, and the pathway regulates several cellular processes that are critical for cancer progression, including metabolism, growth and survival (Courtney et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

et al. 2012

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“…Vock et al ( 27,28 ) examined 0.2 mM oleate for 24 h and 50 M palmitate. They identifi ed subunit of PI3 kinase ( 26 ), suggesting that downregulation of PIK3IP1 might mediate the protective effects of oleate. We fi rst tested the effects of the pharmacologic PI3 kinase inhibitor LY294002 in cells treated with palmitate (0.5 mM) or palmitate and oleate (0.5 mM and 0.25 mM, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…In the current study, oleate adaptation completely abolished the PIK3IP1 transcript response to palmitate in HepG2 cells. PIK3IP1 was recently identifi ed by Zhu et al ( 26 ) as a protein that shows homology to the regulatory p85 subunit of PI3K. PIK3IP1 binds to and negatively regulates the p110 subunit of PI3K, thus acting in place of the p85 regulatory subunit.…”

Section: Discussionmentioning

confidence: 99%

“…PIK3IP1 binds to and negatively regulates the p110 subunit of PI3K, thus acting in place of the p85 regulatory subunit. PIK3IP1 overexpression reduced PI3K activity and thus Akt phosphorylation, whereas a reduction of PIK3IP1 increased PI3K activity and Akt phosphorylation ( 26 ). Inhibition of PI3K, including by increased PIK3IP1, may increase apoptosis in conditions of cellular stress ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

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Distinct gene expression profiles characterize cellular responses to palmitate and oleate

Das

Mondal

Elbein

2010

Journal of Lipid Research

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“…His 6 -tagged PR8/NS1 was generated by partially digesting pGEX'TEV'PR8/NS1 with NcoI/NotI and ligating the ϳ700-bp fragment into the corresponding sites of linearized pEHISTEV. The pGADT7.p110␣-ABD plasmid (expressing HA-tagged p110␣-ABD) was a kind gift from M. DeFrances (University of Pittsburgh) (27). The integrity of all newly generated constructs was confirmed by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

Binding of Influenza A Virus NS1 Protein to the Inter-SH2 Domain of p85β Suggests a Novel Mechanism for Phosphoinositide 3-Kinase Activation

Hale

Batty

Downes

et al. 2008

Journal of Biological Chemistry

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Influenza A virus NS1 protein stimulates host-cell phosphoinositide 3-kinase (PI3K) signaling by binding to the p85␤ regulatory subunit of PI3K. Here, in an attempt to establish a mechanism for this activation, we report further on the functional interaction between NS1 and p85␤. Complex formation was found to be independent of NS1 RNA binding activity and is mediated by the C-terminal effector domain of NS1. Intriguingly, the primary direct binding site for NS1 on p85␤ is the inter-SH2 domain, a coiled-coil structure that acts as a scaffold for the p110 catalytic subunit of PI3K. In vitro kinase activity assays, together with protein binding competition studies, reveal that NS1 does not displace p110 from the inter-SH2 domain, and indicate that NS1 can form an active heterotrimeric complex with PI3K. In addition, it was established that residues at the C terminus of the inter-SH2 domain are essential for mediating the interaction between p85␤ and NS1. Equivalent residues in p85␣ have previously been implicated in the basal inhibition of p110. However, such p85␣ residues were unable to substitute for those in p85␤ with regards NS1 binding. Overall, these data suggest a model by which NS1 activates PI3K catalytic activity by masking a normal regulatory element specific to the p85␤ inter-SH2 domain.Lipid second messengers generated by phosphoinositide 3-kinases (PI3Ks) 2 regulate an array of protein kinase signaling cascades that, in turn, control diverse cellular processes such as cell survival, metabolism, proliferation, and inflammation/immunity (1, 2). Class IA PI3Ks are dimeric enzymes consisting of a p110 catalytic subunit tethered to a smaller, non-catalytic, regulatory subunit (typically p85␣ or p85␤). The interaction of p85 with p110 functions to both stabilize heat-labile p110, and suppress its enzymatic activity (3). Thus, within cells, p85 and p110 proteins exist as obligate heterodimers (3, 4), and subsequent activation of PI3K must occur via inter-or intramolecular allosteric changes.The p85 regulatory subunits contain an N-terminal SH3 (Src homology 3) domain, a BH (B-cell receptor homology) domain flanked by proline-rich sequences, and two SH2 (Src homology 2) domains, which are on either side of the p110-binding inter-SH2 (iSH2) domain (Fig. 1A) (2, 5). All the domains of p85 contribute to the regulation of p110, and stimulatory signals (such as growth factors and hormones) act through multiple mechanisms in order to modulate the basal inhibition of PI3K. For example, tyrosine phosphorylation of consensus YXXM motifs in activated growth factor receptors (or their specific adapter substrates) provides docking sites for the two p85 SH2 domains, and relieves the effect of p85 on p110 (6, 7). Additionally, binding of GTPases (such as Cdc42 and Rac) to the p85 BH domain, or binding of Src family kinases to the p85 proline-rich motifs, have also been shown to increase the activity of the p85:p110 heterodimer (8 -10). In contrast, a novel adapter protein, Ruk, interacts with the N-terminal SH3 domain of ...

show abstract

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

Cited by 71 publications

References 18 publications

Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

Distinct gene expression profiles characterize cellular responses to palmitate and oleate

Binding of Influenza A Virus NS1 Protein to the Inter-SH2 Domain of p85β Suggests a Novel Mechanism for Phosphoinositide 3-Kinase Activation

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