The Interactive Fly

Evolutionarily conserved developmental pathways

Cell growth and survival - The insulin signaling pathway

Organism size is determined by a tightly regulated mechanism that coordinates cell growth, cell proliferation and cell death. The Drosophila insulin receptor/Chico/Dp110 pathway regulates cell and organism size. Chico, an adaptor protein that binds to the insulin receptor, and Phosphotidylinositol 3 kinase 92E (Dp110), an enzyme that phosphorylates lipids, are both involved in transmitting insulin receptor signals downstream to cellular effectors. The the phosphoinositide-3-OH-kinase-dependent serine/threonine protein kinase Akt1 (also known as protein kinase B or PKB) affects cell and organ size in Drosophila in a cell autonomous manner. PKB has a PH domain that binds 3-phosphorylated inositol lipids (phosphatidylinositol 3,4,5-trisphosphate also known as PIP3), and the translocation of the mammalian homolog of Drosophila Akt1 to the plasma membrane is an important part of its activation. Akt appears to stimulate intracellular pathways that specifically regulate cell and compartment size independent of cell proliferation in vivo.

The role of vertebrate PI3K in cell growth and survival is not well understood. One PI3K target is p70S6K (Drosophila homolog RPS6-p70-protein kinase) which in turn controls translation and cell growth. S6K proteins are 40S ribosomal protein kinases, and as such play a key role in the regulation of cell growth by controlling the protein synthetic apparatus, most notably ribosomal proteins. In the case of S6K1, at least eight phosphorylation sites are believed to mediate kinase activation in a hierarchical fashion. Activation is initiated by phosphatidylinositide-3OH kinase (PI3K)-mediated phosphorylation of key residues in the carboxy-terminus of the kinase, allowing phosphorylation of a critical residue residing in the activation loop of the catalytic domain by phosphoinositide-dependent kinase 1 (PDK1). The kinases responsible for phosphorylating the carboxy-terminal sites have yet to be identified. Additionally, S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), a protein also conserved in Drosophila. The TOR proteins may serve an additional function as a checkpoint for amino acid availability.

The human tumor suppressor gene PTEN gets its name from its biochemical function, its domain structure and its chromosomal location: PTEN stands for the combination of phosphatase and tensin homolog on chromosome 10. The protein exhibits phosphatase activity against proteins and lipid phosphate residues. The lipid phosphatase function of PTEN places it in the middle of the insulin pathway, known to involve lipid signaling. Drosophila Pten modulates cell size, and consequently tissue mass, by acting antagonistically to the lipid modifiying enzyme Phosphotidylinositol 3 kinase 92E and its upstream activator Chico. All signals from the insulin receptor can be antagonized by Pten. In terms of its protein phosphatase function, mammalian PTEN targets focal adhesion kinase (see Drosophila Focal adhesion kinase-like), a major effector of cytoskeletal function. Overexpression of wild-type mammalian PTEN and mutant PTEN that lacks lipid phosphatase activity can reduce levels of focal adhesion kinase phosphorylation and the formation of focal adhesions, thereby inhibiting cell migration and invasiveness. In terms of its cytoskeletal connection, Drosophila Pten appears to regulate the subcellular organization of the actin cytoskeleton in multiple cell types. The bristle, hair, and rhabdomere phenotypes observed in Drosophila Pten mutant tissue have not been reported in flies defective in insulin or Dp110 signaling, indicating thatunlike the Pten-linked growth defects, involving insulin signaling, these effects are probably not derived from alterations in lipid signaling but from direct influences on cytoskeletal function.

date revised: 5 December 2000

Developmental Pathways conserved in Evolution

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