PMID- 10064595
OWN - NLM
STAT- MEDLINE
DCOM- 19990429
LR  - 20181201
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 5
DP  - 1999 Mar 1
TI  - Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for
      the regulation of lipid kinases in vitro and in vivo.
PG  - 1292-302
AB  - Phosphoinositide 3-kinases (PI3Ks) are lipid kinases which also possess an in
      vitro protein kinase activity towards themselves or their adaptor proteins. The
      physiological relevance of these phosphorylations is unclear at present. Here,
      the protein kinase activity of the tyrosine kinase-linked PI3K, p110delta, is
      characterized and its functional impact assessed. In vitro autophosphorylation of
      p110delta completely down-regulates its lipid kinase activity. The single site of
      autophosphorylation was mapped to Ser1039 at the C-terminus of p110delta.
      Antisera specific for phospho-Ser1039 revealed a very low level of
      phosphorylation of this residue in cell lines. However, p110delta that is
      recruited to activated receptors (such as CD28 in T cells) shows a time-dependent
      increase in Ser1039 phosphorylation and a concomitant decrease in associated
      lipid kinase activity. Treatment of cells with okadaic acid, an inhibitor of
      Ser/Thr phosphatases, also dramatically increases the level of
      Ser1039-phosphorylated p110delta. LY294002 and wortmannin blocked these in vivo
      increases in Ser1039 phosphorylation, consistent with the notion that PI3Ks, and 
      possibly p110delta itself, are involved in the in vivo phosphorylation of
      p110delta. In summary, we show that PI3Ks are subject to regulatory
      phosphorylations in vivo similar to those identified under in vitro conditions,
      identifying a new level of control of these signalling molecules.
FAU - Vanhaesebroeck, B
AU  - Vanhaesebroeck B
AD  - Ludwig Institute for Cancer Research, 91 Riding House Street, London W1P 8BT, UK.
      bartvanh@ludwig.ucl.ac.uk
FAU - Higashi, K
AU  - Higashi K
FAU - Raven, C
AU  - Raven C
FAU - Welham, M
AU  - Welham M
FAU - Anderson, S
AU  - Anderson S
FAU - Brennan, P
AU  - Brennan P
FAU - Ward, S G
AU  - Ward SG
FAU - Waterfield, M D
AU  - Waterfield MD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Androstadienes)
RN  - 0 (CD28 Antigens)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Phosphatidylinositol 4,5-Diphosphate)
RN  - 0 (Phosphatidylinositols)
RN  - 0 (Phosphopeptides)
RN  - 0 (Recombinant Proteins)
RN  - 17885-08-4 (Phosphoserine)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Amino Acid Sequence
MH  - Androstadienes/pharmacology
MH  - Binding Sites
MH  - CD28 Antigens/metabolism
MH  - Chromones/pharmacology
MH  - Down-Regulation
MH  - Humans
MH  - Jurkat Cells
MH  - Molecular Sequence Data
MH  - Morpholines/pharmacology
MH  - Mutation
MH  - Peptide Mapping
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - Phosphatidylinositol 4,5-Diphosphate/metabolism
MH  - Phosphatidylinositols/metabolism
MH  - Phosphopeptides/analysis
MH  - Phosphorylation
MH  - Phosphoserine/metabolism
MH  - Recombinant Proteins/metabolism
MH  - Sequence Alignment
MH  - Signal Transduction
MH  - Wortmannin
PMC - PMC1171219
EDAT- 1999/03/04 00:00
MHDA- 1999/03/04 00:01
CRDT- 1999/03/04 00:00
PHST- 1999/03/04 00:00 [pubmed]
PHST- 1999/03/04 00:01 [medline]
PHST- 1999/03/04 00:00 [entrez]
AID - 10.1093/emboj/18.5.1292 [doi]
PST - ppublish
SO  - EMBO J. 1999 Mar 1;18(5):1292-302. doi: 10.1093/emboj/18.5.1292.