PMID- 10339425
OWN - NLM
STAT- MEDLINE
DCOM- 19990628
LR  - 20191210
IS  - 0960-9822 (Print)
IS  - 0960-9822 (Linking)
VI  - 9
IP  - 10
DP  - 1999 May 20
TI  - Rapamycin-sensitive phosphorylation of PKC on a carboxy-terminal site by an
      atypical PKC complex.
PG  - 522-9
AB  - BACKGROUND: The protein kinase C (PKC) family has been implicated in the control 
      of many cellular functions. Although PKC isotypes are characterized by their
      allosteric activation, phosphorylation also plays a key role in controlling
      activity. In classical PKC isotypes, one of the three critical sites is a
      carboxy-terminal hydrophobic site also conserved in other AGC kinase subfamily
      members. Although this site is crucial to the control of this class of enzymes,
      the upstream kinase(s) has not been identified. RESULTS: A membrane-associated
      kinase activity that phosphorylates the hydrophobic site in PKCalpha was
      detected. This activity was suppressed when cells were pretreated with the
      immunosuppresant drug rapamycin or the phosphoinositide (Pl) 3-kinase inhibitor
      LY294002. These pretreatments also blocked specifically the serum-induced
      phosphorylation of the hydrophobic site in PKCdelta in vivo. The most highly
      purified hydrophobic site kinase preparations ( approximately 10,000-fold)
      reacted with antibodies to PKCzeta/iota. Consistent with this, rapamycin and
      LY294002 reduced the recovery of PKCzeta from the membrane fraction of
      transfected cells. An activated mutant of PKCzeta, but not wild-type PKCzeta,
      induced phosphorylation of the PKCdelta hydrophobic site in a
      rapamycin-independent manner, whereas a kinase-dead PKCzeta mutant suppressed
      this serum-induced phosphorylation. The immunopurified, activated mutant of
      PKCzeta could phosphorylate the PKCdelta hydrophobic site in vitro, whereas
      wild-type PKCzeta could not. CONCLUSIONS: PKCzeta is identified as a component of
      the upstream kinase responsible for the phosphorylation of the PKCdelta
      hydrophobic site in vitro and in vivo. PKCzeta can therefore control the
      phosphorylation of this PKCdelta site, antagonizing a rapamycin-sensitive
      pathway.
FAU - Ziegler, W H
AU  - Ziegler WH
AD  - Protein Phosphorylation Laboratory, Imperial Cancer Research Fund, 44 Lincoln's
      Inn Fields, London, WC2A 3PX, UK.
FAU - Parekh, D B
AU  - Parekh DB
FAU - Le Good, J A
AU  - Le Good JA
FAU - Whelan, R D
AU  - Whelan RD
FAU - Kelly, J J
AU  - Kelly JJ
FAU - Frech, M
AU  - Frech M
FAU - Hemmings, B A
AU  - Hemmings BA
FAU - Parker, P J
AU  - Parker PJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Curr Biol
JT  - Current biology : CB
JID - 9107782
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Cell Line
MH  - Chromones/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Morpholines/pharmacology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Kinase C/chemistry/*metabolism
MH  - Rats
MH  - Serine/metabolism
MH  - Sirolimus/*pharmacology
MH  - Substrate Specificity
EDAT- 1999/05/26 00:00
MHDA- 1999/05/26 00:01
CRDT- 1999/05/26 00:00
PHST- 1999/05/26 00:00 [pubmed]
PHST- 1999/05/26 00:01 [medline]
PHST- 1999/05/26 00:00 [entrez]
AID - S0960-9822(99)80236-X [pii]
AID - 10.1016/s0960-9822(99)80236-x [doi]
PST - ppublish
SO  - Curr Biol. 1999 May 20;9(10):522-9. doi: 10.1016/s0960-9822(99)80236-x.