The p38 SAPK pathway is required for Ha-ras induced in vitro invasion of NIH3T3 cells.
Constitutive activation of the ras oncoprotein plays a critical role in cancer invasion and metastasis. Particularly, ras-related protease expression such as the serine protease urokinase plasminogen activator (u-PA) has been implicated in mediating cancer cell invasion. Previous studies have shown that ras-mediated u-PA expression is regulated through the mitogen- (MAPK) and stress-activated protein kinase (SAPK) signal transduction pathways extracellular signal-regulated kinase (ERK) and c-Jun-activating kinase (JNK). We therefore asked the question, if ras-related cell invasion might additionally require the third MAPK/SAPK signal transduction cascade, p38. Indeed, we found that ras induces invasion based on the activation of certain p38 protein kinase isoforms, in particular, p38alpha. Moreover, ras activation through transient or stable expression of a Ha-rasEJ mutant induced the expression of u-PA. This was found to be a consequence of an increase of u-PA m-RNA, which was paralleled by only a modest activation of the u-PA promoter. In conclusion, we provide evidence for the requirement of a novel ras-p38alpha-u-PA pathway for ras-dependent cellular invasion.
Behren
Andreas
A
Department of Otolaryngology, Head and Neck Surgery, The University of Tuebingen, Elfriede-Aulhornstrasse 5, 72076 Tuebingen, Germany.
Binder
Konrad
K
Vucelic
Goran
G
Herberhold
Stephan
S
Hirt
Bernhard
B
Loewenheim
Hubert
H
Preyer
Serena
S
Zenner
Hans Peter
HP
Simon
Christian
C
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology*
D007093:Imidazoles; D007527:Isoenzymes; D011725:Pyridines; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; C093642:SB 203580