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MEK1 mediates a positive feedback on Raf-1 activity independently of Ras and Src.
Oncogene 15, 1503-1511 (1997)
Growth factor stimulated receptor tyrosine kinases activate a protein kinase cascade via the serine/threonine protein kinase Raf-1. Direct upstream activators of Raf-1 are Ras and Src. This study shows that MEK1, the direct downstream effector of Raf-1, can also stimulate Raf-1 kinase activity by a positive feedback loop. Activated MEK1 mediates hyperphosphorylation of the amino terminal regulatory as well as of the carboxy terminal catalytic domain of Raf-1. The hyperphosphorylation of Raf-1 correlates with a change in the tryptic phosphopeptide pattern only at the carboxy terminus of Raf-1 and an increase in Raf-1 kinase activity. MEK1-mediated Raf-1 activation is inhibited by co-expression of the MAPK specific phosphatase MKP-1 indicating that the MEK1 effect is exerted through a MAPK dependent pathway. Stimulation of Raf-1 activity by MEK1 is independent of Ras, Src and tyrosine phosphorylation of Raf-1. MEK1 can however synergize with Ras and leads to further increase of the Raf-1 kinase activity. Thus, MEK1 can mediate activation of Raf-1 by a novel positive feedback mechanism which allows fast signal amplification and could prolong activation of Raf-1.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Feedback Loop ; Mek1 ; Mitogen-activated Protein Kinase Cascade ; Raf-1 Activation
ISSN (print) / ISBN
0950-9232
e-ISSN
0950-9232
Zeitschrift
Oncogene
Quellenangaben
Band: 15,
Heft: 13,
Seiten: 1503-1511
Verlag
Nature Publishing Group
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed