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Identification of an adaptor for the Drosophila Class IA phosphoinositide 3-kinase and the study of its function in vivo and in vitro

Weinkove, David; (1999) Identification of an adaptor for the Drosophila Class IA phosphoinositide 3-kinase and the study of its function in vivo and in vitro. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Class IA phosphoinositide 3-kinases (PI3Ks) regulate several cellular processes in response to receptor tyrosine kinase (RTK) activation. This response is mediated by the SH2 domain-containing adaptors for Class IA PI3Ks, which, by binding to phosphotyrosines on activated RTKs or their substrates, bring Class IA PI3Ks close to their lipid substrates at the membrane. This thesis describes the identification of p60, the adaptor for the Drosophila Class IA PI3K, Dp110. p60 was isolated by affinity purification with a phosphopeptide derived from a human RTK, and the corresponding cDNA was cloned using peptide sequence data. Like the mammalian Class IA PI3K adaptors, p60 possesses two SH2 domains, which enable receptor binding, and an inter-SH2 domain, which facilitates Dp110 binding. Biochemical analyses showed that the Dp110/p60 complex is widely expressed and possesses lipid and protein kinase activity. After determining the genomic structure of the p60 region and characterising candidate mutations, two p60 mutants were generated. Zygotic p60 mutants, like Dp110 mutants, showed a lethal phenotype resulting from defective larval development. Clones of p60 or Dp110 mutant cells survived and proliferated during imaginal disc development, but were reduced in both size and number. To address its in vivo function further, p60 was ectopically expressed in eye and wing imaginal discs. Previously, it was shown that ectopically-expressed Dp110 promotes imaginal disc growth. In contrast, p60 ectopic expression resulted in small wings and eyes. Expressed together, Dp110 and p60 had little effect on growth, even though the proteins were present at higher levels when coexpressed than when expressed alone. Together, these results demonstrate a specific function for Dp110/p60 in imaginal disc development. Models for the regulation of Dp110 by p60 and the control of organ growth by Dp110/p60 are proposed, and their implications for mammalian Class IA PI3K function are discussed.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Identification of an adaptor for the Drosophila Class IA phosphoinositide 3-kinase and the study of its function in vivo and in vitro
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Phosphoinositide 3-kinases
URI: https://discovery.ucl.ac.uk/id/eprint/10102356
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