The Drosophila insulin/IGF receptor controls growth and size by modulating PtdInsP(3) levels.
Understanding the control of size is of fundamental biological and clinical importance. Insulin/IGF signaling during development controls growth and size, possibly by coordinating the activities of the Ras and PI 3-kinase signaling pathways. We show that in Drosophila mutating the consensus binding site for the Ras pathway adaptor Drk/Grb2 in Chico/IRS does not interfere with growth whereas mutating the binding sites of the PI 3-kinase adaptor p60 completely abrogates Chico function. Furthermore, we present biochemical and genetic evidence that loss of the homolog of the tumor suppressor gene, Pten, results in increased PtdInsP(3) levels and that these increased levels are sufficient to compensate for the complete loss of the Insulin/insulin-like growth factor receptor function. This reduction of Pten activity is also sufficient to vastly increase organism size. These results suggest that PtdInsP(3) is a second messenger for growth and that levels of PtdInsP(3) during development regulate organismal size.
Oldham
Sean
S
Universität Zürich, Zoologisches Institut, Winterthurerstrasse 190, CH - 8057, Switzerland.
Stocker
Hugo
H
Laffargue
Muriel
M
Wittwer
Franz
F
Wymann
Matthias
M
Hafen
Ernst
E
D000595:Amino Acid Sequence; D000818:Animals; D001824:Body Constitution / Q000502:physiology; D002352:Carrier Proteins; D004330:Drosophila / Q000254:growth & development*; D029721:Drosophila Proteins / Q000502:physiology; D005260:Female; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011972:Receptor, Insulin / Q000502:physiology*; D017451:Receptors, Somatomedin / Q000502:physiology*; D015290:Second Messenger Systems; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D002352:Carrier Proteins; D029721:Drosophila Proteins; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018129:Phosphatidylinositol Phosphates; D017451:Receptors, Somatomedin; D025521:Tumor Suppressor Proteins; C120233:chico protein, Drosophila; C055525:phosphatidylinositol 3-phosphate; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D020929:Mitogen-Activated Protein Kinase Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase