Disease relevance of Pi3K68D

• TRB3 expression is remarkably reduced in prostate cancer PC-3 cells after inhibition of PI 3-kinase [1].
• We also report that PI3K controls the expression and localization of synaptic markers in human neuroblastoma cells, suggesting that PI3K synaptogenic activity is conserved in humans [2].

High impact information on Pi3K68D

• Thus, Dp110 integrates inputs from its phosphotyrosine-binding adaptor and Ras to achieve maximal PI(3)K signalling in specific biological situations [3].
• The Drosophila class I PI(3)K, Dp110, is activated by nutrient-responsive insulin signalling and modulates growth, oogenesis and metabolism [3].
• In contrast, using both laser ablation and a novel wounding assay that allows localized treatment with inhibitory drugs, we show that PI3K is essential for hemocyte chemotaxis toward wounds and that Pvf signals and PDGF/VEGF receptor expression are not required for this rapid chemotactic response [4].
• These results indicate that the endogenous PI3K_68D may act antagonistically to the EGF receptor-stimulated Ras-mitogen-activated protein kinase pathway and downstream of, or parallel to, the Notch receptor [5].
• A class II polyproline motif in PI3K_68D can bind the Drk adaptor protein in vitro, primarily via the N-terminal SH3 domain of Drk [5].

Biological context of Pi3K68D

• Biochemical analyses demonstrate that PI3K_68D has a novel substrate specificity in vitro, restricted to phosphatidylinositol and phosphatidylinositol 4-phosphate, and is unable to phosphorylate phosphatidylinositol (4,5)-bisphosphate, the implied in vivo substrate for p110 [6].
• Additionally, a PI 3-kinase activity which generates phosphatidylinositol 3-phosphate has been shown to be required for protein trafficking in yeast [6].
• PI3K_68D has the potential to bind to signalling molecules containing SH3 domains, lacks p85-adaptor-binding sequences, has a Ca(2+)-independent phospholipid-binding domain and displays a restricted in vitro substrate specificity, so it could define a novel signal transduction pathway [6].
• Wild-type and catalytically inactive PI3K_68D transgenes have opposite effects on the number of sensory bristles and on wing venation phenotypes induced by modified epidermal growth factor (EGF) receptor signaling [5].
• The N termini of the Cpk proteins do not contain any recognizable protein motif, while the C termini contain "C2 domains," a feature unique among PtdIns kinases [7].

Anatomical context of Pi3K68D

• We report here the cloning of a novel PI 3-kinase, p170, from cDNA of insulin-sensitive mouse 3T3-L1 adipocytes [8].
• Thus DOCK180 contained a phosphoinositide-binding domain, as did the other guanine nucleotide exchange factors with a Dbl homology domain, and was translocated to the plasma membrane on the activation of PI-3K [9].
• We show here that the levels of phosphoinositide 3 kinase (PI3K) regulate synapse number in both Drosophila larval motor neurons and adult brain projection neurons [2].
• Previous work in our laboratory has indicated that the steroid hormone ecdysone triggers programmed autophagy in the fat body of Drosophila larvae by downregulating the class I phosphoinositide 3-kinase (PI3K) pathway [10].

Associations of Pi3K68D with chemical compounds

• The PI3K_68D cDNA encodes a protein of 210 kDa, which lacks sequences implicated in linking p110 PI 3-kinases to p85 adaptor proteins, but contains an amino-terminal proline-rich sequence, which could bind to SH3 domains, and a carboxy-terminal C2 domain [6].
• Cpk is a novel class of Drosophila PtdIns 3-kinase containing a C2 domain [7].
• This finding suggests that Cpk function may be regulated by tyrosine kinases [7].
• Cpk has an intrinsic PtdIns kinase activity and can phosphorylate PtdIns and PtdIns-4-P, but not PtdIns(4,5)P2, at the D3 position of the inositol ring [7].
• TRB3 expression is furthermore controlled by nutrient supplies: Both the lack of glucose or amino acids results in a substantial increase in TRB3 protein levels in a PI 3-kinase-dependent manner [1].

References