LNK (SH2B3): paradoxical effects in ovarian cancer.
LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant hematopoietic cells. In these cells, it downregulates activated tyrosine kinases at the cell surface resulting in an antiproliferative effect. To date, no studies have examined activities of LNK in solid tumors. In this study, we found by in silico analysis and staining tissue arrays that the levels of LNK expression were elevated in high-grade ovarian cancer. To test the functional importance of this observation, LNK was either overexpressed or silenced in several ovarian cancer cell lines. Remarkably, overexpression of LNK rendered the cells resistant to death induced by either serum starvation or nutrient deprivation, and generated larger tumors using a murine xenograft model. In contrast, silencing of LNK decreased ovarian cancer cell growth in vitro and in vivo. Western blot studies indicated that overexpression of LNK upregulated and extended the transduction of the mitogenic signal, whereas silencing of LNK produced the opposite effects. Furthermore, forced expression of LNK reduced cell size, inhibited cell migration and markedly enhanced cell adhesion. Liquid chromatography-mass spectroscopy identified 14-3-3 as one of the LNK-binding partners. Our results suggest that in contrast to the findings in hematologic malignancies, the adaptor protein LNK acts as a positive signal transduction modulator in ovarian cancers.
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
L-W
LW
Ding
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Q-Y
QY
Sun
1] Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore [2] Division of Hematology/Oncology, Cedar-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
D-C
DC
Lin
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
W
W
Chien
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
N
N
Hattori
School of Biology Science, Nanyang Technological University, Singapore, Singapore.
X-M
XM
Dong
Division of Hematology/Oncology, Cedar-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
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S
Gery
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
M
M
Garg
Santa Monica-University of California, Los Angeles Medical Center, Los Angeles, CA, USA.
N B
NB
Doan
Santa Monica-University of California, Los Angeles Medical Center, Los Angeles, CA, USA.
J W
JW
Said
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
J-F
JF
Xiao
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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H
Yang
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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LZ
Liu
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
X
X
Meng
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
R Y-J
RY
Huang
School of Biology Science, Nanyang Technological University, Singapore, Singapore.
K
K
Tang
1] Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore [2] Division of Hematology/Oncology, Cedar-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA [3] National University Cancer Institute, National University Hospital Singapore, Singapore, Singapore.
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HP
Koeffler
D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D048429:Cell Size; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000473:pathology*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human; C482982:YWHAB protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases