Prolonged activation of ERK2 by epidermal growth factor and other growth factors requires a functional insulin-like growth factor 1 receptor.
We have investigated the activation of ERK2, a serine/threonine kinase necessary for transmission of mitogenic signals, in cells derived from mouse embryos homozygous for a null mutation of the insulin-like growth factor (IGF)-1R gene (R- cells) and from wild-type littermates (W cells), respectively. Stimulation of quiescent W cells with IGF-1, epidermal growth factor (EGF), or with a combination growth factors induced both a maximal transient and a prolonged activation of ERK2, whereas platelet-derived growth factor or a combination of platelet-derived growth factor and EGF resulted only in transient activation of ERK2. In contrast, stimulation of R cells with IGF-1, EGF, or combinations of growth factors resulted in a transient and submaximal activation of ERK2. Reintroduction of a wild-type human IGF-1R or of a C-terminus IGF-1R mutant, but not of a juxtamembrane mutant IGF-1R, into R- cells was able to restore ERK2 activation to wild-type levels. Thus, prolonged ERK2 activation in mouse embryo fibroblasts stimulated with purified growth factors is largely dependent on a signal generated by the IGF-1R.
Swantek
J L
JL
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Baserga
R
R
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D010446:Peptide Fragments / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017451:Receptors, Somatomedin / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D006133:Growth Substances; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D017451:Receptors, Somatomedin; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1