PMID- 9028336
OWN - NLM
STAT- MEDLINE
DCOM- 19970311
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 89
IP  - 3
DP  - 1997 Feb 1
TI  - Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in 
      human neutrophils. I. Tyrosine phosphorylation-dependent stimulation of 
      phosphatidylinositol 3-kinase and inhibition by phorbol esters.
PG  - 1035-44
AB  - Phosphatidylinositol 3-kinase (PI3-kinase) is a cytosolic enzyme that plays key 
      roles in mediating signaling through many receptors. The heterodimeric form of 
      PI3-kinase is made up of a regulatory subunit, p85, and a catalytic subunit, 
      p110. Although granulocyte-macrophage colony-stimulating factor (GM-CSF) has been 
      shown to activate PI3-kinase, the mechanisms by which this activation is mediated 
      and regulated are incompletely understood. Here we show that treatment of human 
      neutrophils with GM-CSF induced both time- and concentration-dependent increases 
      in the level of tyrosine phosphorylation of p85. The ability of GM-CSF to 
      activate PI3-kinase was abolished by pretreating the cells with erbstatin, a 
      tyrosine kinase inhibitor. The simultaneous treatment of the cells with GM-CSF 
      and phorbol esters such as phorbol 12-myristate 13-acetate (PMA) and phorbol 
      12,13-dibutyrate (PDBu) significantly inhibited both the tyrosine phosphorylation 
      of p85 and the activation of PI3-kinase. The inhibitory effects of phorbol esters 
      were not induced by their inactive analogues and they were selective to the 
      stimulation of tyrosine phosphorylation of p85 since phorbol esters did not alter 
      the enhancement of the pattern of tyrosine phosphorylation of other cellular 
      proteins, including that of Jak2 induced by GM-CSF. However, PMA significantly 
      inhibited the in situ tyrosine phosphorylation and the activation of lyn observed 
      in response to GM-CSF. The results suggest that the activation of PI3-kinase by 
      GM-CSF is mediated by the tyrosine phosphorylation of p85 and that this 
      activation is downregulated by PKC possibly via the inhibition of lyn.
FAU - al-Shami, A
AU  - al-Shami A
AD  - Centre de Recherche en Rhumatologie et Immunologie, Faculty of Medicine, Laval 
      University, Ste-Foy, Quebec, Canada.
FAU - Bourgoin, S G
AU  - Bourgoin SG
FAU - Naccache, P H
AU  - Naccache PH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Phorbol Esters)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Adult
MH  - Enzyme Activation/drug effects
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/*pharmacology
MH  - Humans
MH  - Janus Kinase 2
MH  - Neutrophil Activation/*drug effects
MH  - Neutrophils/drug effects/*enzymology/*metabolism
MH  - Phorbol Esters/*pharmacology
MH  - Phosphatidylinositol 3-Kinases
MH  - Phosphorylation/drug effects
MH  - Phosphotransferases (Alcohol Group Acceptor)/*antagonists & 
      inhibitors/*metabolism
MH  - Phosphotyrosine/*physiology
MH  - Protein-Tyrosine Kinases/drug effects
MH  - *Proto-Oncogene Proteins
MH  - Signal Transduction/*drug effects
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - src-Family Kinases/drug effects
EDAT- 1997/02/01 00:00
MHDA- 1997/02/01 00:01
CRDT- 1997/02/01 00:00
PHST- 1997/02/01 00:00 [pubmed]
PHST- 1997/02/01 00:01 [medline]
PHST- 1997/02/01 00:00 [entrez]
AID - S0006-4971(20)58908-8 [pii]
PST - ppublish
SO  - Blood. 1997 Feb 1;89(3):1035-44.