Signaling molecules involved in coupling growth hormone receptor to mitogen-activated protein kinase activation.
We have shown previously that GH stimulates the mitogen-activated protein (MAP) kinases designated ERKs (extracellular signal-regulated kinases) 1 and 2. To examine pathways coupling GH receptor (GHR) to MAP kinase activation, we have determined the effects of GH on SHC-growth factor receptor bound 2-son of Sevenless (SHC-Grb2-SOS) association and activation of Ras, Raf, and MAP-ERK kinase (MEK). GH promoted the rapid, transient association of SHC with the Grb2-SOS complex, which correlated with the time course of Ras, Raf, and MEK activation. Despite the continuous presence of GH, these activation events were transient with Ras, Raf, and MEK returning to near basal activity by 15 or 30 min. The inactivation of Ras, Raf, and MEK directly correlated with the serine/threonine phosphorylation of SOS and dissociation of SOS from Grb2 but not Grb2 from tyrosine-phosphorylated SHC. Phosphorylation was blocked by the MEK inhibitor, PD98059. Based upon the established functions of the MAP kinase pathway, these data indicate that GH stimulation results in the assembly of a SHC-Grb2-SOS complex that serves to activate Ras and thereby engage the Raf-MEK-ERK pathway. Activation of this pathway generates a feedback kinase cascade that phosphorylates SOS resulting in the dissociation of SHC-Grb2 complexes from SOS, thereby causing a more rapid termination of the signaling pathway than would result from SHC dephosphorylation.
Vanderkuur
J A
JA
Department of Physiology, The University of Michigan Medical School, Ann Arbor 48109-0622, USA.
Butch
E R
ER
Waters
S B
SB
Pessin
J E
JE
Guan
K L
KL
Carter-Su
C
C
D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D013006:Growth Hormone / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D008934:Mitogens / Q000494:pharmacology*; D010766:Phosphorylation; D011233:Precipitin Tests; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf; D011986:Receptors, Somatotropin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020664:Son of Sevenless Proteins; D013997:Time Factors; D018631:ras Proteins / Q000502:physiology
D004791:Enzyme Inhibitors; D005419:Flavonoids; D008565:Membrane Proteins; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D020664:Son of Sevenless Proteins; D013006:Growth Hormone; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one