Increase in hepatocyte growth factor receptor tyrosine kinase activity in renal carcinoma cells is associated with increased motility partly through phosphoinositide 3-kinase activation

被引:27
作者
Nakamura, T
Kanda, S
Yamamoto, K
Kohno, T
Maeda, K
Matsuyama, T
Kanetake, H
机构
[1] Nagasaki Univ, Sch Med, Dept Urol, Nagasaki 8528501, Japan
[2] Nagasaki Univ, Grad Sch Med, Dept Mol Microbiol & Immunol, Div Cytokine Signaling, Nagasaki 8528523, Japan
[3] Nagasaki Univ, Grad Sch Med, Div Endothelial Cell Biol, Nagasaki 8528501, Japan
基金
日本学术振兴会;
关键词
renal carcinoma cells; motility; HGF; HGF receptor; PI3-kinase;
D O I
10.1038/sj.onc.1204975
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Dysregulated cell motility is one of the major characteristics of invasion and metastatic potentials of malignant tumor cells. Here, we examined the hepatocyte growth factor (HGF)-induced cell motility of two human renal carcinoma cell lines, ACHN and VMRC-RCW. Scattering and migration was induced in ACHN in an HGF-dependent manner, whereas they were maintained in VMRC-RCW even in the absence of HGF. In VMRC-RCW, HGF receptor (HGFR) tyrosine kinase was constitutively active, and sequence analysis showed N375S, A1209G and V1290L mutations. However, transfection experiments using porcine aortic endothelial (PAE) cells demonstrated that no single mutation or combination of two or three mutations caused HGF-independent constitutive activation. Conversely, the expressed amount of receptor protein had a pivotal role in the basal kinase activity. With respect to downstream signaling molecules of HGFR in ACHN or VMRC-RCW, the Ras-MAPK pathway was downregulated, whereas phosphoinositide 3-kinase (PI3-kinase) was not further activated by HGF-treatment in VMRC-RCW cells. The PI3-kinase inhibitors, wortmannin and LY294002 strongly inhibited spontaneous migration of VMRC-RCW. One transfected PAE cell line with massive overexpression of HGFR demonstrated scattered morphology and increased PI3-kinase activity in association with increased motility, which was partially inhibited by LY294002. Taken together, our results indicate that the overexpression of HGFR causes increase in cellular motility and PI3-kinase shows the important contribution on the increased motility of renal carcinoma cells.
引用
收藏
页码:7610 / 7623
页数:14
相关论文
共 77 条
[21]   Hepatocyte growth factor scatter factor Met signaling in tumorigenicity and invasion/metastasis [J].
Jeffers, M ;
Rong, S ;
VandeWoude, GF .
JOURNAL OF MOLECULAR MEDICINE-JMM, 1996, 74 (09) :505-513
[22]   HEPATOCYTE GROWTH-FACTOR HEPATOPOIETIN-A STIMULATES THE GROWTH OF RAT-KIDNEY PROXIMAL TUBULE EPITHELIAL-CELLS (RPTE), RAT NONPARENCHYMAL LIVER-CELLS, HUMAN-MELANOMA CELLS, MOUSE KERATINOCYTES AND STIMULATES ANCHORAGE-INDEPENDENT GROWTH OF SV40-TRANSFORMED RPTE [J].
KAN, M ;
ZHANG, GH ;
ZARNEGAR, R ;
MICHALOPOULOS, G ;
MYOKEN, Y ;
MCKEEHAN, WL ;
STEVENS, JL .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 174 (01) :331-337
[23]   The nonreceptor protein-tyrosine kinase c-Fes is involved in fibroblast growth factor-2-induced chemotaxis of murine brain capillary endothelial cells [J].
Kanda, S ;
Lerner, EC ;
Tsuda, S ;
Shono, T ;
Kanetake, H ;
Smithgall, TE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (14) :10105-10111
[24]   Phosphatidylinositol 3'-kinase-independent p70 S6 kinase activation by fibroblast growth factor receptor-1 is important for proliferation but not differentiation of endothelial cells [J].
Kanda, S ;
Hodgkin, MN ;
Woodfield, RJ ;
Wakelam, MJO ;
Thomas, G ;
ClaessonWelsh, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (37) :23347-23353
[25]   HEPATOCYTE GROWTH-FACTOR PREVENTS ACUTE-RENAL-FAILURE AND ACCELERATES RENAL REGENERATION IN MICE [J].
KAWAIDA, K ;
MATSUMOTO, K ;
SHIMAZU, H ;
NAKAMURA, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) :4357-4361
[26]   AUTOCRINE STIMULATION OF INTRACELLULAR PDGF RECEPTORS IN V-SIS TRANSFORMED-CELLS [J].
KEATING, MT ;
WILLIAMS, LT .
SCIENCE, 1988, 239 (4842) :914-916
[27]   THE C-TERMINAL SH2 DOMAIN OF P85 ACCOUNTS FOR THE HIGH-AFFINITY AND SPECIFICITY OF THE BINDING OF PHOSPHATIDYLINOSITOL 3-KINASE TO PHOSPHORYLATED PLATELET-DERIVED GROWTH-FACTOR-BETA RECEPTOR [J].
KLIPPEL, A ;
ESCOBEDO, JA ;
FANTL, WJ ;
WILLIAMS, LT .
MOLECULAR AND CELLULAR BIOLOGY, 1992, 12 (04) :1451-1459
[28]   Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering [J].
Kodama, A ;
Matozaki, T ;
Fukuhara, A ;
Kikyo, M ;
Ichihashi, M ;
Takai, Y .
MOLECULAR BIOLOGY OF THE CELL, 2000, 11 (08) :2565-2575
[29]   Constitutive activation of the prolactin receptor results in the induction of growth factor-independent proliferation and constitutive activation of signaling molecules [J].
Lee, RCH ;
Walters, JA ;
Reyland, ME ;
Anderson, SM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (15) :10024-10034
[30]  
Levine M D, 1995, EXS, V74, P157