PMID- 10205168
OWN - NLM
STAT- MEDLINE
DCOM- 19990611
LR  - 20181113
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 8
DP  - 1999 Apr 15
TI  - Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf
      activation.
PG  - 2137-48
AB  - The Raf family of serine/threonine protein kinases couple growth factor receptor 
      stimulation to mitogen activated protein kinase activation, but their own
      regulation is poorly understood. Using phospho-specific antisera, we show that
      activated Raf-1 is phosphorylated on S338 and Y341. Expression of Raf-1 with
      oncogenic Ras gives predominantly S338 phosphorylation, whereas activated Src
      gives predominantly Y341 phosphorylation. Phosphorylation at both sites is
      maximal only when both oncogenic Ras and activated Src are present. Raf-1 that
      cannot interact with Ras-GTP is not phosphorylated, showing that phosphorylation 
      is Ras dependent, presumably occurring at the plasma membrane. Mutations which
      prevent phosphorylation at either site block Raf-1 activation and maximal
      activity is seen only when both are phosphorylated. Mutations at S339 or Y340 do 
      not block Raf-1 activation. While B-Raf lacks a tyrosine phosphorylation site
      equivalent to Y341 of Raf-1, S445 of B-Raf is equivalent to S338 of Raf-1.
      Phosphorylation of S445 is constitutive and is not stimulated by oncogenic Ras.
      However, S445 phosphorylation still contributes to B-Raf activation by elevating 
      basal and consequently Ras-stimulated activity. Thus, there are considerable
      differences between the activation of the Raf proteins; Ras-GTP mediates two
      phosphorylation events required for Raf-1 activation but does not regulate such
      events for B-Raf.
FAU - Mason, C S
AU  - Mason CS
AD  - CRC Centre for Cell and Molecular Biology, Institute of Cancer Research, 237
      Fulham Road, London SW3 6JB.
FAU - Springer, C J
AU  - Springer CJ
FAU - Cooper, R G
AU  - Cooper RG
FAU - Superti-Furga, G
AU  - Superti-Furga G
FAU - Marshall, C J
AU  - Marshall CJ
FAU - Marais, R
AU  - Marais R
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  - 42HK56048U (Tyrosine)
RN  - 452VLY9402 (Serine)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Animals
MH  - COS Cells
MH  - Cell Membrane/metabolism
MH  - Epidermal Growth Factor/pharmacology
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-raf/*metabolism
MH  - Serine/*metabolism
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Tyrosine/*metabolism
PMC - PMC1171298
EDAT- 1999/04/16 00:00
MHDA- 1999/04/16 00:01
CRDT- 1999/04/16 00:00
PHST- 1999/04/16 00:00 [pubmed]
PHST- 1999/04/16 00:01 [medline]
PHST- 1999/04/16 00:00 [entrez]
AID - 10.1093/emboj/18.8.2137 [doi]
PST - ppublish
SO  - EMBO J. 1999 Apr 15;18(8):2137-48. doi: 10.1093/emboj/18.8.2137.