Identification and characterization of a novel MAP kinase kinase kinase, MLTK.
The MAPK cascades regulate a wide variety of cellular functions, including cell proliferation, differentiation, and stress responses. Here we have identified a novel MAP kinase kinase kinase (MAPKKK), termed MLTK (for MLK-like mitogen-activated protein triple kinase), whose expression is increased by activation of the ERK/MAPK pathway. There are two alternatively spliced forms of MLTK, MLTKalpha and MLTKbeta. When overexpressed in cells, both MLTKalpha and MLTKbeta are able to activate the ERK, JNK/SAPK, p38, and ERK5 pathways. Moreover, both MLTKalpha and MLTKbeta are activated in response to osmotic shock with hyperosmolar media through autophosphorylation. Remarkably, expression of MLTKalpha, but not MLTKbeta, in Swiss 3T3 cells results in the disruption of actin stress fibers and dramatic morphological changes. A kinase-dead form of MLTKalpha does not cause these phenomena. Inhibition of the p38 pathway significantly blocks MLTKalpha-induced stress fiber disruption and morphological changes. These results suggest that MLTK is a stress-activated MAPKKK that may be involved in the regulation of actin organization.
Gotoh
I
I
Department of Biophysics, Graduate School of Science, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Adachi
M
M
Nishida
E
E
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017931:DNA Primers; D018076:DNA, Complementary; D006863:Hydrogen-Ion Concentration; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009997:Osmotic Pressure; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid; D048051:p38 Mitogen-Activated Protein Kinases
D000199:Actins; D017931:DNA Primers; D018076:DNA, Complementary; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C428384:MLK-like mitogen-activated protein triple kinase