The Drosophila insulin receptor activates multiple signaling pathways but requires insulin receptor substrate proteins for DNA synthesis.
The Drosophila insulin receptor (DIR) contains a 368-amino-acid COOH-terminal extension that contains several tyrosine phosphorylation sites in YXXM motifs. This extension is absent from the human insulin receptor but resembles a region in insulin receptor substrate (IRS) proteins which binds to the phosphatidylinositol (PI) 3-kinase and mediates mitogenesis. The function of a chimeric DIR containing the human insulin receptor binding domain (hDIR) was investigated in 32D cells, which contain few insulin receptors and no IRS proteins. Insulin stimulated tyrosine autophosphorylation of the human insulin receptor and hDIR, and both receptors mediated tyrosine phosphorylation of Shc and activated mitogen-activated protein kinase. IRS-1 was required by the human insulin receptor to activate PI 3-kinase and p70s6k, whereas hDIR associated with PI 3-kinase and activated p70s6k without IRS-1. However, both receptors required IRS-1 to mediate insulin-stimulated mitogenesis. These data demonstrate that the DIR possesses additional signaling capabilities compared with its mammalian counterpart but still requires IRS-1 for the complete insulin response in mammalian cells.
Yenush
L
L
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Fernandez
R
R
Myers
M G
MG
Grammer
T C
TC
Sun
X J
XJ
Blenis
J
J
Pierce
J H
JH
Schlessinger
J
J
White
M F
MF
D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000494:pharmacology*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D019000:Phosphotyrosine / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004247:DNA; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D011972:Receptor, Insulin; D011994:Recombinant Proteins; D019893:Ribosomal Protein S6 Kinases; D013936:Thymidine; C526292:IRS1 protein, human