Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway

Abstract

The human tumor suppressor gene PTEN encodes a putative cytoskeleton-associated molecule with both protein phosphatase and phosphatidylinositol 3,4,5-trisphosphate (PIP3) 3-phosphatase activities. In cell culture, the lipid phosphatase activity of this protein is involved in regulating cell proliferation and survival, but the mechanism by which PTEN inhibits tumorigenesis in vivo is not fully established. Here we show that the highly evolutionarily conserved Drosophila PTEN homolog, DPTEN, suppresses hyperplastic growth in flies by reducing cell size and number. We demonstrate that DPTEN modulates tissue mass by acting antagonistically to the Drosophila Class I phosphatidylinositol 3-kinase, Dp110, and its upstream activator Chico, an insulin receptor substrate homolog. Surprisingly, although DPTEN does not generally affect cell fate determination, it does appear to regulate the subcellular organization of the actin cytoskeleton in multiple cell types. From these data, we propose that DPTEN has a complex role in regulating tissue and body size. It acts in opposition to Dp110 to control cell number and growth, while coordinately influencing events at the cell periphery via its effects on the actin cytoskeleton.

Angiotensin II as candidate of cardiac cachexia

“…SHIP-2 over-expression blocks hypertrophy in muscle [36,38] and SHIP-2 knockout mice died after birth because of increased insulin sensitivity and hypoglycemia as a result of an increase in Akt2 activity [39]. Similarly, overexpression of PTEN inactivates Akt1 [40] and causes a reduction in cell size [41][42][43]. Conversely, expression of a dominant-negative mutant form of PTEN in the heart induces cardiac hypertrophy [44].…”

The role of PTEN signaling perturbations in cancer and in targeted therapy

“…The Drosophila DPTEN gene affects lifespan when expressed from the fat body of the head (Hwangbo et al, 2004). In addition to this, DPTEN also regulates proliferation, cell size and cytoskeletal remodeling (Goberdhan et al, 1999). The roles of PTEN in mammalian systems are far reaching as it profoundly affects development, metabolism and tumor progression (Di Cristofano et al, 1998;Stambolic et al, 1998;Podsypanina et al, 1999;Accili and Arden, 2004;Kitamura et al, 2005).…”

PTEN targeting: the search for novel insulin sensitisers provides new insight into obesity research

“…Much of this work was prompted by the finding that DAF18, the Caenorhabditis elegans PTEN homologue, downregulates insulin receptor-like signalling in the worm [11]. Insulin signalling is also negatively regulated by PTEN in Drosophila melanogaster [12].…”