Novel signal transduction pathway for luteinizing hormone and its interaction with insulin: activation of Janus kinase/signal transducer and activator of transcription and phosphoinositol 3-kinase/Akt pathways.
The actions of LH are mediated through a single class of cell surface LH/human chorionic gonadotropin receptor, which is a member of the G protein-coupled receptor family. In the present study we showed that LH induced rapid tyrosine phosphorylation and activation of the Janus kinase 2 (JAK2) in rat ovary. Upon JAK2 activation, tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1), STAT-5b, insulin receptor substrate-1 (IRS-1), and Src homology and collagen homology (Shc) were detected. In addition, LH induced IRS-1/phosphoinositol 3-kinase and Shc /growth factor receptor-binding protein 2 (Grb2) associations and downstream AKT (protein kinase B, homologous to v-AKT) serine phosphorylation and ERK tyrosine phosphorylation, respectively. The simultaneous infusion of insulin and LH induced higher phosphorylation levels of JAK2, STAT5b, IRS-1, and AKT compared with each hormone alone in the whole ovary of normal rats. By immunohistochemistry we demonstrated that these late events take place in follicular cells and both external and internal theca. These results indicate a new signal transduction pathway for LH and show that there is positive cross-talk between the insulin and LH signaling pathways at the level of phosphoinositol 3-kinase/AKT pathway in this tissue.
Carvalho
Carla R O
CR
Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, 13081-970 Campinas, Brazil.
Carvalheira
José B C
JB
Lima
Maria H M
MH
Zimmerman
Suzana F
SF
Caperuto
Luciana C
LC
Amanso
Angélica
A
Gasparetti
Alessandra L
AL
Meneghetti
Vainer
V
Zimmerman
Leonardo F
LF
Velloso
Licio A
LA
Saad
Mario J A
MJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D053614:Janus Kinase 2; D007986:Luteinizing Hormone / Q000378:metabolism* / Q000494:pharmacology; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010053:Ovary / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000502:physiology; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology
D004268:DNA-Binding Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D053614:Janus Kinase 2; D007986:Luteinizing Hormone; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; C526292:IRS1 protein, human; C526296:Irs1 protein, rat; C494081:Stat1 protein, rat; C494097:Stat5b protein, rat; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; C494920:Akt1 protein, rat