Epidermal growth factor receptor is involved in clusterin-induced astrocyte proliferation.
We previously reported that clusterin enhances astrocyte proliferation and extracellular signal-regulated kinase (ERK) activity. It, however, remains largely unknown how clusterin promotes cell growth. Here, we investigate the signaling pathway and related molecules underlying astrocyte proliferation by clusterin. Exogenous clusterin stimulates Ras-dependent Raf-1/mitogen-activated protein kinase kinase (MEK)/ERK activation. Clusterin-induced astrocyte proliferation and ERK1/2 phosphorylation were abrogated by either AG1478 (an inhibitor of epidermal growth factor receptor, EGFR) or EGFR small interfering RNA. Furthermore, clusterin treatment provoked tyrosine phosphorylation of EGFR (pY(1173)), which was also blocked by AG1478. These results suggest that clusterin requires EGFR activation to deliver its mitogenic signal through the Ras/Raf-1/MEK/ERK signaling cascade in astrocytes.
Shim
Young-Jun
YJ
Department of Pharmacology, BK21 Program for Medical Sciences, College of Medicine, Korea University, Seoul, Korea.
Shin
Yong-Jae
YJ
Jeong
Seong-Yun
SY
Kang
Sang-Wook
SW
Kim
Byeong-Moo
BM
Park
In-Sun
IS
Min
Bon-Hong
BH
D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051152:Clusterin / Q000494:pharmacology* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects; D011799:Quinazolines; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
D051152:Clusterin; D008934:Mitogens; D011799:Quinazolines; D034741:RNA, Small Interfering; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases