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P85? phosphoinositide 3-kinase subunit regulates tumor progression.

ABSTRACT: PIK3R2 encodes a ubiquitous regulatory subunit (p85?) of PI3K, an enzyme that generates 3-polyphosphoinositides at the plasma membrane. PI3K activation triggers cell survival and migration. We found that p85? expression is elevated in breast and colon carcinomas and that its increased expression correlates with PI3K pathway activation and tumor progression. p85? expression induced moderate PIP(3) generation at the cell membrane and enhanced cell invasion. In accordance, genetic alteration of pik3r2 expression levels modulated tumor progression in vivo. Increased p85? expression thus represents a cellular strategy in cancer progression.

SUBMITTER: Cortes I

PROVIDER: S-EPMC3396516 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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p85β phosphoinositide 3-kinase subunit regulates tumor progression.

Cortés Isabel I Sánchez-Ruíz Jesús J Zuluaga Susana S Calvanese Vincenzo V Marqués Miriam M Hernández Carmen C Rivera Teresa T Kremer Leonor L González-García Ana A Carrera Ana C AC

Proceedings of the National Academy of Sciences of the United States of America 20120625 28

PIK3R2 encodes a ubiquitous regulatory subunit (p85β) of PI3K, an enzyme that generates 3-polyphosphoinositides at the plasma membrane. PI3K activation triggers cell survival and migration. We found that p85β expression is elevated in breast and colon carcinomas and that its increased expression correlates with PI3K pathway activation and tumor progression. p85β expression induced moderate PIP(3) generation at the cell membrane and enhanced cell invasion. In accordance, genetic alteration of pik ...[more]

PMID: 22733740

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Non-catalytic role of phosphoinositide 3-kinase in mesenchymal cell migration through non-canonical induction of p85β/AP-2-mediated endocytosis.

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Non-catalytic role of phosphoinositide 3-kinase in mesenchymal cell migration through non-canonical induction of p85β/AP-2-mediated endocytosis.

Project description:Class IA phosphoinositide 3-kinase (PI3K) galvanizes fundamental cellular processes such as migration, proliferation, and differentiation. To enable multifaceted roles, the catalytic subunit p110 utilizes a multidomain, regulatory subunit p85 through its inter SH2 domain (iSH2). In cell migration, their product PI(3,4,5)P3 generates locomotive activity. While non-catalytic roles are also implicated, underlying mechanisms and its relationship to PI(3,4,5)P3 signaling remain elusive. Here, we report that a disordered region of iSH2 contains previously uncharacterized AP-2 binding motifs which can trigger clathrin and dynamin-mediated endocytosis independent of PI3K catalytic activity. The AP-2 binding motif mutants of p85 aberrantly accumulate at focal adhesions and upregulate both velocity and persistency in fibroblast migration. We thus propose the dual functionality of PI3K in the control of cell motility, catalytic and non-catalytic, arising distinctly from juxtaposed regions within iSH2.

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p85beta phosphoinositide 3-kinase regulates CD28 coreceptor function.

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Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway.

Project description:Phosphoinositide-dependent kinase-1 (PDK-1) is a central mediator of the cell signaling between phosphoinositide 3-kinase (PI3K) and various intracellular serine/threonine kinases including Akt/protein kinase B (PKB), p70 S6 kinases, and protein kinase C. Recent studies with cell transfection experiments have implied that PDK-1 may be involved in various cell functions including cell growth and apoptosis. However, despite its pivotal role in cellular signalings, the in vivo functions of PDK-1 in a multicellular system have rarely been investigated. Here, we have isolated Drosophila PDK-1 (dPDK-1) mutants and characterized the in vivo roles of the kinase. Drosophila deficient in the dPDK-1 gene exhibited lethality and an apoptotic phenotype in the embryonic stage. Conversely, overexpression of dPDK-1 increased cell and organ size in a Drosophila PI3K-dependent manner. dPDK-1 not only could activate Drosophila Akt/PKB (Dakt1), but also substitute the in vivo functions of its mammalian ortholog to activate Akt/PKB. This functional interaction between dPDK-1 and Dakt1 was further confirmed through genetic analyses in Drosophila. On the other hand, cAMP-dependent protein kinase, which has been proposed as a possible target of dPDK-1, did not interact with dPDK-1. In conclusion, our findings provide direct evidence that dPDK-1 regulates cell growth and apoptosis during Drosophila development via the PI3K-dependent signaling pathway and demonstrate our Drosophila system to be a powerful tool for elucidating the in vivo functions and targets of PDK-1.

| S-EPMC33436 | biostudies-literature

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