scholarly journals Participation of prolactin receptors and phosphatidylinositol 3-kinase and MAP kinase pathways in the increase in pancreatic islet mass and sensitivity to glucose during pregnancy

2004 ◽  
Vol 183 (3) ◽  
pp. 469-476 ◽  
Author(s):  
Maria E C Amaral ◽  
Daniel A Cunha ◽  
Gabriel F Anhê ◽  
Mirian Ueno ◽  
Everardo M Carneiro ◽  
...  
Keyword(s):  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Antisense Oligonucleotide ◽  
Janus Kinase ◽  
Serine Phosphorylation ◽  
Phosphatidylinositol 3 Kinase ◽  
Pregnant Rats ◽  
Islet Mass ◽  
And Control ◽  
Phosphatidylinositol 3

Prolactin (PRL) exerts its biological effects mainly by activating the Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) signaling pathway. We have recently demonstrated that PRL also stimulates the insulin receptor substrates/phosphatidylinositol 3-kinase (IRSs/PI3K) and SH2-plekstrin homology domain (SHC)/ERK pathways in islets of neonatal rats. In the present study, we investigated the involvement of the PI3K and MAP kinase (MAPK) cascades in islet development and growth in pregnant rats. The protein expression of AKT1, p70S6K and SHC was higher in islets from pregnant compared with control rats. Higher basal levels of tyrosine phosphorylation were found in classic transducers of insulin cell signaling (IRS1, IRS2 and SHC). Increased levels of threonine/tyrosine phosphorylation of ERK1/2 and serine phosphorylation of AKT and p70S6K were also detected. To assess the participation of PRL in these phenomena, pregnant and control rats were treated with an antisense oligonucleotide to reduce the expression of the PRL receptor (PRLR). Phosphorylation of AKT was reduced in islets from pregnant and control rats, whereas p70S6K protein levels were reduced only in islets from treated pregnant rats. Finally, glucose-induced insulin secretion was reduced in islets from pregnant but not from control rats treated with the PRLR antisense oligonucleotide. In conclusion, downstream proteins of the PI3K (AKT and p70S6K) and MAPK (SHC and ERK1/2) cascades are regulated by PRL signaling in islets from pregnant rats. These findings indicate that these pathways participate in the increase in islet mass and the sensitivity to glucose during pregnancy.

Peptide antisera to human colony-stimulating factor 1 receptor detect ligand-induced conformational changes and a binding site for phosphatidylinositol 3-kinase

1991 ◽  
Vol 11 (5) ◽  
pp. 2489-2495
Author(s):  
J R Downing ◽  
S A Shurtleff ◽  
C J Sherr
Keyword(s):  
Binding Site ◽  
Tyrosine Phosphorylation ◽  
Stable Complex ◽  
Colony Stimulating Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Lipid Kinase ◽  
Vitro Assay ◽  
Juxtamembrane Region ◽  
Stimulating Factor ◽  
Phosphatidylinositol 3

A peptide antiserum (anti-A) directed to the intracellular, juxtamembrane region (residues 552 to 574) of the human colony-stimulating factor 1 receptor (CSF-1R) precipitated only ligand-activated, native receptors from solution but bound to unstimulated forms after their denaturation. Two peptide antisera (anti-KI1 and -KI2), directed to residues 679 to 700 and 701 to 721, respectively, in the CSF-1R kinase insert (KI) domain and including mapped sites of ligand-induced phosphorylation at Tyr-699 and Tyr-708, bound at least 80% of the receptor molecules expressed in either CSF-1-stimulated or unstimulated cells. Immune complexes formed with anti-KI1, anti-A, or a peptide antiserum to the CSF-1R carboxyl terminus (anti-C-ter) coprecipitated CSF-1R complexed to a phosphatidylinositol 3-kinase (PtdIns 3-K) from CSF-1-stimulated cells, whereas anti-KI2 serum did not. In an in vitro assay, binding of CSF-1R to PtdIns 3-K required receptor tyrosine phosphorylation but not CSF-1R-mediated phosphorylation of the lipid kinase, and the association was specifically blocked by anti-KI2 or antibodies to phosphotyrosine. Neither anti-KI1, anti-A, nor anti-C-ter serum inhibited binding. We conclude that (i) only a minority of ligand-activated receptors form a stable complex with PtdIns 3-K in vivo, (ii) efficient binding of the lipid kinase requires receptor tyrosine phosphorylation within the CSF-1R KI domain, and (iii) a region within the KI domain defined by residues 701 to 721 at least partially overlaps the PtdIns 3-K binding site.

scholarly journals Tyrosine Phosphorylation of p85 Relieves Its Inhibitory Activity on Phosphatidylinositol 3-Kinase

2001 ◽  
Vol 276 (29) ◽  
pp. 27455-27461 ◽  
Author(s):  
Bruce D. Cuevas ◽  
Yiling Lu ◽  
Muling Mao ◽  
Jinyi Zhang ◽  
Ruth LaPushin ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Inhibitory Activity ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

Erythropoietin Induces the Tyrosine Phosphorylation of GAB1 and Its Association With SHC, SHP2, SHIP, and Phosphatidylinositol 3-Kinase

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2578-2585 ◽  
Author(s):  
Carinne Lecoq-Lafon ◽  
Frédérique Verdier ◽  
Serge Fichelson ◽  
Stany Chrétien ◽  
Sylvie Gisselbrecht ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Intracellular Signaling ◽  
Direct Consequence ◽  
Receptor Activation ◽  
Phosphatidylinositol 3 Kinase ◽  
Erythroid Progenitors ◽  
Epo Receptor ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Phosphatidylinositol 3

Abstract Five tyrosine-phosphorylated proteins with molecular masses of 180, 145, 116, 100, and 70 kD are associated with phosphatidylinositol 3-kinase (PI 3-kinase) in erythropoietin (Epo)-stimulated UT-7 cells. The 180- and 70-kD proteins have been previously shown to be IRS2 and the Epo receptor. In this report, we show that the 116-kD protein is the IRS2-related molecular adapter, GAB1. Indeed, Epo induced the transient tyrosine phosphorylation of GAB1 in UT-7 cells. Both kinetics and Epo dose-response experiments showed that GAB1 tyrosine phosphorylation was a direct consequence of Epo receptor activation. After tyrosine phosphorylation, GAB1 associated with the PI 3-kinase, the phosphotyrosine phosphatase SHP2, the phosphatidylinositol 3,4,5 trisphosphate 5-phosphatase SHIP, and the molecular adapter SHC. GAB1 was also associated with the molecular adapter GRB2 in unstimulated cells, and this association dramatically increased after Epo stimulation. Thus, GAB1 could be a scaffold protein able to couple the Epo receptor activation with the stimulation of several intracellular signaling pathways. Epo-induced tyrosine phosphorylation of GAB1 was also observed in normal human erythroid progenitors isolated from cord blood. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and thrombopoietin (TPO) also induced the tyrosine phosphorylation of GAB1 in UT-7 cells, indicating that this molecule participates in the signal transduction of several cytokine receptors.

c-Src and Phosphatidylinositol 3-Kinase Are Involved in NGF-Dependent Tyrosine Phosphorylation of Shc in PC12 Cells

1998 ◽  
Vol 250 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Ken-ichi Sato ◽  
Tetsuji Otsuki ◽  
Miwa Kimoto ◽  
Miki Kakumoto ◽  
Alexander A. Tokmakov ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Pc12 Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals The Integrin β1 Subunit Transmembrane Domain Regulates Phosphatidylinositol 3-Kinase-dependent Tyrosine Phosphorylation of Crk-associated Substrate

2004 ◽  
Vol 15 (6) ◽  
pp. 2558-2567 ◽  
Author(s):  
Annika Armulik ◽  
Teet Velling ◽  
Staffan Johansson
Keyword(s):  
Amino Acid ◽  
Tyrosine Phosphorylation ◽  
Transmembrane Domain ◽  
Basic Amino Acid ◽  
Proximal Part ◽  
Phosphatidylinositol 3 Kinase ◽  
Integrin Β1 ◽  
Downstream Target ◽  
Mediate Cell ◽  
Phosphatidylinositol 3

Our previous studies on the transmembrane domain of human integrin subunits have shown that a conserved basic amino acid in both subunits of integrin heterodimers is positioned in the plasma membrane in the absence of interacting proteins. To investigate the possible functional role of the lipid-embedded lysine in the mouse integrin β1 subunit, this amino acid was replaced with leucine, and the mutated β1 subunit (β1AK756L) was stably expressed in β1-deficient GD25 cells. The extracellular domain of β1AK756L integrins possesses a competent conformation for ligand binding as determined by the ability to mediate cell adhesion, and by the presence of the monoclonal antibody 9EG7 epitope. However, the spreading of GD25-β1AK756L cells on fibronectin and laminin-1 was impaired, and the rate of migration of GD25-β1AK756L cells on fibronectin was reduced compared with GD25-β1A cells. Phosphorylation of tyrosines in focal adhesion kinase (FAK) and the Y416 in c-Src in response to β1AK756L-mediated adhesion was similar to that induced by wild-type β1. The tyrosine phosphorylation level of paxillin, a downstream target of FAK/Src, was unaffected by the β1 mutation, whereas tyrosine phosphorylation of CAS was strongly reduced. The results demonstrate that CAS is a target for phosphorylation both by FAK-dependent and -independent pathways after integrin ligation. The latter pathway was inhibited by wortmannin and LY294002, implicating that it required an active phosphatidylinositol 3-kinase. Furthermore, the K756L mutation in the β1 subunit was found to interfere with β1-induced activation of Akt. The results from this study identify phosphatidylinositol 3-kinase as an early component of a FAK-independent integrin signaling pathway triggered by the membrane proximal part of the β1 subunit.

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