Mitogen-activated protein kinase-dependent and -independent routes control shedding of transmembrane growth factors through multiple secretases

Juan Carlos Montero; Laura Yuste; Elena Díaz-Rodríguez; Azucena Esparís-Ogando; Atanasio Pandiella

doi:10.1042/0264-6021:3630211

Mitogen-activated protein kinase-dependent and -independent routes control shedding of transmembrane growth factors through multiple secretases

Biochem J. 2002 Apr 15;363(Pt 2):211-21. doi: 10.1042/0264-6021:3630211.

Authors

Juan Carlos Montero¹, Laura Yuste, Elena Díaz-Rodríguez, Azucena Esparís-Ogando, Atanasio Pandiella

Affiliation

¹ Instituto de Microbiología Bioquímica and Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Avenida del Campo Charro s/n, Salamanca 37007, Spain.

Abstract

Solubilization of a number of membrane proteins occurs by the action of cell-surface proteases, termed secretases. Recently, the activity of these secretases has been reported to be controlled by the extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and the p38 mitogen-activated protein kinase (MAPK) routes. In the present paper, we show that shedding of membrane-anchored growth factors (MAGFs) may also occur through MAPK-independent routes. In Chinese-hamster ovary cells, cleavage induced by protein kinase C (PKC) stimulation was largely insensitive to inhibitors of the ERK1/ERK2 and p38 routes. Other reagents such as sorbitol or UV light stimulated MAGF cleavage independent of PKC. The action of sorbitol on cleavage was only partially prevented by the combined action of inhibitors of the p38 and ERK1/ERK2 routes, indicating that sorbitol can also stimulate shedding by MAPK-dependent and -independent routes. Studies in cells devoid of activity of the secretase tumour necrosis factor-alpha-converting enzyme (TACE) indicated that this protease had an essential role in PKC- and ERK1/ERK2-mediated shedding. However, secretases other than TACE may also cleave MAGFs since sorbitol could still induce shedding in these cells. These observations suggest that cleavage of MAGFs is a complex process in which multiple secretases, activated through different MAPK-dependent and -independent routes, are involved.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM Proteins
ADAM17 Protein
Amyloid Precursor Protein Secretases
Animals
Aspartic Acid Endopeptidases
CHO Cells
Cell Line
Cell Membrane / drug effects
Cell Membrane / metabolism*
Cell Membrane / radiation effects
Cricetinae
Endopeptidases / metabolism*
Growth Substances / metabolism*
Metalloendopeptidases / antagonists & inhibitors
Metalloendopeptidases / metabolism
Mice
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / metabolism*
Neuregulin-1 / metabolism
Protease Inhibitors / pharmacology
Protein Kinase C / metabolism
Protein Precursors / metabolism
Rats
Solubility
Sorbitol / pharmacology
Tetradecanoylphorbol Acetate / pharmacology
Transforming Growth Factor alpha / metabolism
Ultraviolet Rays
p38 Mitogen-Activated Protein Kinases

Substances

Growth Substances
Neuregulin-1
Protease Inhibitors
Protein Precursors
Transforming Growth Factor alpha
Sorbitol
Protein Kinase C
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
Bace1 protein, mouse
ADAM Proteins
Metalloendopeptidases
ADAM17 Protein
Adam17 protein, mouse
Adam17 protein, rat
Tetradecanoylphorbol Acetate