Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK

A Minden; A Lin; M McMahon; C Lange-Carter; B Dérijard; R J Davis; G L Johnson; M Karin

doi:10.1126/science.7992057

Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK

Science. 1994 Dec 9;266(5191):1719-23. doi: 10.1126/science.7992057.

Authors

A Minden¹, A Lin, M McMahon, C Lange-Carter, B Dérijard, R J Davis, G L Johnson, M Karin

Affiliation

¹ Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla 92093-0636.

PMID: 7992057
DOI: 10.1126/science.7992057

Abstract

Growth factors activate mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs) and Jun kinases (JNKs). Although the signaling cascade from growth factor receptors to ERKs is relatively well understood, the pathway leading to JNK activation is more obscure. Activation of JNK by epidermal growth factor (EGF) or nerve growth factor (NGF) was dependent on H-Ras activation, whereas JNK activation by tumor necrosis factor alpha (TNF-alpha) was Ras-independent. Ras activates two protein kinases, Raf-1 and MEK (MAPK, or ERK, kinase) kinase (MEKK). Raf-1 contributes directly to ERK activation but not to JNK activation, whereas MEKK participated in JNK activation but caused ERK activation only after overexpression. These results demonstrate the existence of two distinct Ras-dependent MAPK cascades--one initiated by Raf-1 leading to ERK activation, and the other initiated by MEKK leading to JNK activation.

Publication types

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

MeSH terms

3T3 Cells
Animals
Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
Enzyme Activation / drug effects
Epidermal Growth Factor / pharmacology
Genes, ras
HeLa Cells
Humans
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 1*
Mice
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases*
Nerve Growth Factors / pharmacology
PC12 Cells
Protein Serine-Threonine Kinases / metabolism*
Protein-Tyrosine Kinases / metabolism*
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-raf
Rats
Transfection
Tumor Necrosis Factor-alpha / pharmacology
ras Proteins / pharmacology*

Substances

Nerve Growth Factors
Proto-Oncogene Proteins
Tumor Necrosis Factor-alpha
Epidermal Growth Factor
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-raf
Calcium-Calmodulin-Dependent Protein Kinases
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 1
MAP3K1 protein, human
Map3k1 protein, mouse
ras Proteins