GH and epidermal growth factor signaling in normal and Laron syndrome fibroblasts.
We have investigated and compared GH and epidermal growth factor (EGF) signaling in primary human skin fibroblasts from normal subjects and subjects with GH-binding protein-positive Laron syndrome (LS). In normal human fibroblasts, GH and EGF activate the tyrosine phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT5b; in LS fibroblasts, EGF does, but GH does not. GH also activates the tyrosine phosphorylation of Janus kinase (JAK)2 in normal, but not LS, fibroblasts. Similarly, both GH and EGF activate MAPK in normal fibroblasts, but only EGF does in the LS fibroblasts. As in the 3T3-F442A mouse preadipocyte cell line, GH signaling to mitogen-activated protein kinase is partially inhibited by wortmannin treatment, indicating a role for phosphatidylinositol 3-kinase (PI3K) in this signaling pathway. The exogenous expression of the GH receptor in one family of LS fibroblasts (H1) but not the other (M) restores signaling to a STAT5 reporter element. Together, these results indicate that the mechanism of defective GH signaling in two families of LS fibroblasts are different but that both occur at a level close to, and specific for, the GH receptor.
Silva
Corinne M
CM
Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville 22908, USA. cms3e@virginia.edu
Kloth
Michael T
MT
Whatmore
Andrew J
AJ
Freeth
James S
JS
Anderson
Neil
N
Laughlin
Kristen K
KK
Huynh
Trang
T
Woodall
Alyson J
AJ
Clayton
Peter E
PE
D000015:Abnormalities, Multiple / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D015153:Blotting, Western; D002648:Child; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D053614:Janus Kinase 2; D008156:Luciferases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013577:Syndrome; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D007202:Indicators and Reagents; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D014443:Tyrosine; D004815:Epidermal Growth Factor; D013006:Growth Hormone; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin