Phosphoinositide 3-kinases: A conserved family of signal transducers

Vanhaesebroeck, Bart; Leevers, Sally J.; Panayotou, George; Waterfield, Michael D.

doi:10.1016/s0968-0004(97)01061-x

Cited by 873 publications

(708 citation statements)

References 49 publications

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“…27 PI3K is a conserved family of lipid kinases that catalyze the phosphorylation of the position 3 of the inositol ring of phosphoinositides. [28][29][30] They produce lipids that are involved in cell proliferation, differentiation, apoptosis, autophagy, cytoskeletal organization, and membrane trafficking. Three classes of PI3K have been defined so far.…”

Section: Discussionmentioning

confidence: 99%

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

et al. 2004

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Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 lM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein lightchain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H þ -ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

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Section: Discussionmentioning

confidence: 99%

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

et al. 2004

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“…As well as an SH3 domain and a bcr/rac GAP homology domain, the p85 regulatory subunit of PtdIns 3-kinase contains two SH2 domains that are capable of binding to a tyrosinephosphorylated peptide with a YXXM motif. This binding results in activation of the associated p110 catalytic subunit of the enzyme [22,23].Insulin receptor substrate-1 (IRS-1) is one of the typical molecules that activate PtdIns 3-kinase via the SH2±YXXM interaction [25]. IRS-1 was originally thought to be the sole substrate of the insulin receptor kinase, but structurally and Correspondence to T. Fujioka, The…”

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confidence: 99%

“…PtdIns 3-kinase is a lipid (and serine) kinase capable of phosphorylating phosphatidylinositol (PtdIns), PtdIns(4)P and PtdIns(4,5)P 2 to produce PtdIns(3)P, PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 , respectively, although the major product in vivo is PtdIns(3,4,5)P 3 (reviewed in [21,22]). The initially discovered form of PtdIns 3-kinase (currently referred to as`Class I A ' [22,23]) consists of a regulatory (p85) and a catalytic (p110) subunit and is specifically inhibited by a fungal metabolite, wortmannin [24]. As well as an SH3 domain and a bcr/rac GAP homology domain, the p85 regulatory subunit of PtdIns 3-kinase contains two SH2 domains that are capable of binding to a tyrosinephosphorylated peptide with a YXXM motif.…”

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confidence: 99%

Involvement of insulin receptor substrates in epidermal growth factor induced activation of phosphatidylinositol 3‐kinase in rat hepatocyte primary culture

Fujioka

2001

European Journal of Biochemistry

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Short-term incubation of adult rat hepatocytes with epidermal growth factor (EGF) caused tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 when the cells had been submitted to primary culture from 1±18 h. Tyrosine-phosphorylated IRS-1 and IRS-2 bound to the regulatory subunit (p85) of phosphatidylinositol (PtdIns) 3-kinase, thereby activating the enzymic activity. Tyrosine phosphorylation of the IRSs and activation of PtdIns 3-kinase in 3 h cultured hepatocytes both proceeded similarly to the same actions of insulin; the activation was rapid and transient, with peak values at 15±30 s and with similar EC 50 s in the nm range in both cases. A possible involvement of insulin receptors in these insulin-like actions of EGF was excluded by the following three lines of evidence. Insulin caused tyrosine phosphorylation of the insulin receptor b-subunit but EGF did not. In contrast, the EGF receptor was phosphorylated by EGF, but the insulin receptor was not. The actions of EGF, but not those of insulin, were inhibited by AG1478, a selective inhibitor of EGF receptor tyrosine kinase. Cultured hepatocytes exposed to insulin or insulin-like growth factor-I (IGF-I) for a short period responded to the subsequent addition of EGF, whereas EGF-treated cells responded to insulin. The cells, however, displayed receptor desensitization under the same conditions, that is, no response was observed upon repeated addition of the same agonist, EGF, insulin or IGF-I. Thus, the EGF receptor-initiated signalling was mediated by PtdIns 3-kinase associated with tyrosine-phosphorylated IRSs in short-term cultured rat hepatocytes.Keywords: signal transduction; tyrosine kinase receptor; tyrosine phosphorylation.Membrane receptors having intrinsic protein tyrosine kinase activity are known to be responsible for promoting proliferation of hepatocytes [1] as well as many other types of cells [2]. If kept in a serum-free medium, DNA synthesis in hepatocytes occurs with the addition of growth factors, among which epidermal growth factor (EGF) is effective in vivo and in culture [3,4] as a result of its binding to typical tyrosine kinase related receptors. The EGF receptor (EGFR) is the prototype of the type I ErbB subfamily, which includes three additional members, ErbB-2/Neu, ErbB3 and ErbB4 [5]. All members of the ErbB subfamily have a domain that serves as a docking site for specific SH-2 domains, which are present in signalling proteins such as the p85 regulatory subunit of phosphatidylinositol (PtdIns) 3-kinase. EGF has been shown to activate PtdIns 3-kinase, although it does not bind directly to the EGFR but is instead activated via association with p120 cbl [6,7] or Gab1 [8], which are phosphorylated on tyrosine residues by the growth factor. PtdIns 3-kinase may also interact with heterodimers of other members of the EGFR family, such as ErbB3, in response to EGF [9,10].PtdIns 3-kinase plays important roles in a wide variety of biological responses to hormones, growth factors and cytokines [11]. The typical responses s...

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“…PI3K phosphorylates PI(4,5)P 2 to create PI(3,4,5,)P 3 [33] and SHIP2 is a negative regulator of the PI3K pathway [17] that dephosphorylates PI(3,4,5)P 3 lipids to PI(3,4)P 2 [15]. Importantly, as shown previously by us, Arap3 binds PI(3,4,5,)P 3 stronger than it binds PI(3,4)P 2 [3].…”

Section: Discussionmentioning

confidence: 99%

The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner

Raaijmakers

Deneubourg

Rehmann

et al. 2007

Cellular Signalling

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Arap3 is a phosphoinositide (PI) 3 kinase effector that serves as a GTPase activating protein (GAP) for both Arf and Rho G-proteins. The protein has multiple pleckstrin homology (PH) domains that bind preferentially phosphatidyl-inositol-3,4,5-trisphosphate (PI(3,4,5,)P 3 ) to induce translocation of Arap3 to the plasma membrane upon PI3K activation. Arap3 also contains a Ras association (RA) domain that interacts with the small G-protein Rap1 and a sterile alpha motif (SAM) domain of unknown function. In a yeast two-hybrid screen for new interaction partners of Arap3, we identified the PI 5′-phosphatase SHIP2 as an interaction partner of Arap3. The interaction between Arap3 and SHIP2 was observed with endogenous proteins and shown to be mediated by the SAM domain of Arap3 and SHIP2. In vitro, these two domains show specificity for a heterodimeric interaction. Since it was shown previously that Arap3 has a higher affinity for PI(3,4,5,)P 3 than for PI(3,4)P 2 , we propose that the SAM domain of Arap3 can function to recruit a negative regulator of PI3K signaling into the effector complex.

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Phosphoinositide 3-kinases: A conserved family of signal transducers

Cited by 873 publications

References 49 publications

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells

Involvement of insulin receptor substrates in epidermal growth factor induced activation of phosphatidylinositol 3‐kinase in rat hepatocyte primary culture

The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner

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