PMID- 10601018
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20161124
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 24
DP  - 1999 Dec 15
TI  - Ectodomain shedding of TGF-alpha and other transmembrane proteins is induced by
      receptor tyrosine kinase activation and MAP kinase signaling cascades.
PG  - 6962-72
AB  - A variety of transmembrane proteins, such as transforming growth factor-alpha
      (TGF-alpha), tumor necrosis factor-alpha (TNF-alpha) and L-selectin, undergo
      shedding, i.e. cleavage of the ectodomain, resulting in release of a soluble
      protein. Although the physiological relevance of ectodomain shedding is well
      recognized, little is known about the signaling mechanisms activating this
      process. We show that growth factor activation of cell surface tyrosine kinase
      receptors induces ectodomain cleavage of transmembrane TGF-alpha through
      activation of the Erk MAP kinase signaling cascade without the need for new
      protein synthesis. In addition, expression of constitutively activated MEK1 or
      its downstream target Erk2 MAP kinase was sufficient to stimulate TGF-alpha
      shedding. The basal cleavage level in the absence of exogenous growth factor
      stimulation was due to p38 MAP kinase signaling. Accordingly, a constitutively
      activated MKK6, a p38 activator, activated TGF-alpha shedding in the absence of
      exogenous stimuli. In addition to TGF-alpha shedding, these mechanisms also
      mediate L-selectin and TNF-alpha cleavage. Thus, L-selectin shedding by
      neutrophils, induced by N-formylmethionyl-leucyl-phenylalanine, was strongly
      inhibited by inhibitors of Erk MAP kinase or p38 MAP kinase signaling. Our
      results indicate that activation of Erk and p38 signaling pathways may represent 
      a general physiological mechanism to induce shedding of a variety of
      transmembrane proteins.
FAU - Fan, H
AU  - Fan H
AD  - Department of Growth Development, Program in Cell Biology, University of
      California at San Francisco, San Francisco, CA 94143, USA.
FAU - Derynck, R
AU  - Derynck R
LA  - eng
GR  - R01 CA54826/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Butadienes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nitriles)
RN  - 0 (Pyridines)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Transforming Growth Factor alpha)
RN  - 0 (U 0126)
RN  - 126880-86-2 (L-Selectin)
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP2K1 protein, human)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - PVX798P8GI (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole)
SB  - IM
MH  - Animals
MH  - Butadienes/pharmacology
MH  - CHO Cells
MH  - Cricetinae
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - L-Selectin/blood
MH  - MAP Kinase Kinase 1
MH  - Membrane Proteins/*metabolism
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - N-Formylmethionine Leucyl-Phenylalanine/pharmacology
MH  - Neutrophils/drug effects/*physiology
MH  - Nitriles/pharmacology
MH  - Protein Processing, Post-Translational
MH  - *Protein-Serine-Threonine Kinases
MH  - Pyridines/pharmacology
MH  - Receptor Protein-Tyrosine Kinases/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Signal Transduction/*physiology
MH  - Transfection
MH  - Transforming Growth Factor alpha/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases
PMC - PMC1171759
EDAT- 1999/12/22 00:00
MHDA- 1999/12/22 00:01
CRDT- 1999/12/22 00:00
PHST- 1999/12/22 00:00 [pubmed]
PHST- 1999/12/22 00:01 [medline]
PHST- 1999/12/22 00:00 [entrez]
AID - 10.1093/emboj/18.24.6962 [doi]
PST - ppublish
SO  - EMBO J. 1999 Dec 15;18(24):6962-72. doi: 10.1093/emboj/18.24.6962.