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The human Sef-a isoform utilizes different mechanisms to regulate receptor tyrosine kinase signaling pathways and subsequent cell fate
Year:
2006
Source of publication :
Journal of Biological Chemistry
Authors :
שבתאי, אריאל
;
.
Volume :
281
Co-Authors:
Ziv, I., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Fuchs, Y., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Preger, E., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Shabtay, A., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel, Dept. of Cattle and Genetic Sciences, Institute of Animal Science, Agricultural Research Organization Newe-Ya'ar Research Center, Ramat Yishay 30095, Israel
Harduf, H., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel, Laboratory for Research in Reproductive Sciences, Dept. of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, Israel, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Zilpa, T., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Dym, N., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Ron, D., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Facilitators :
From page:
39225
To page:
39235
(
Total pages:
11
)
Abstract:
Negative feedback is among the key mechanisms for regulating receptor tyrosine kinase (RTK) signaling. Human Sef, a recently identified inhibitor of RTK signaling, encodes different isoforms, including a membrane spanning (hSef-a) and a cytosolic (hSef-b) isoform. Previously, we reported that hSef-b inhibited fibroblast proliferation and prevented the activation of mitogen-activated protein kinase (MAPK), without affecting protein kinase B/Akt or p38 MAPK. Conflicting results were reported concerning hSef-a inhibition of MAPK activation, and the effect of hSef-a on other RTK-induced signaling pathways is unknown. Here we show that, in fibroblasts, similar to hSef-b, ectopic expression of hSef-a inhibited fibroblast growth factor-induced cell proliferation. Unlike hSef-b, however, the growth arrest was mediated via a MAPK-independent mechanism, and was accompanied by elevated p38 MAPK phosphorylation and inhibition of protein kinase B/Akt. In addition, hSef-a, but not hSef-b, mediated apoptosis in fibroblast growth factor-stimulated cells. Chemical inhibitor of p38 MAPK abrogated the effect of hSef-a on apoptosis. In epithelial cells, ectopic expression of hSef-a inhibited the activation of MAPK, whereas downregulation of endogenous hSef-a significantly increased MAPK activation and accelerated growth factor-dependent cell proliferation. These results indicate that hSef-a is a multifunctional negative modulator of RTK signaling and clearly demonstrate that hSef-a can inhibit the activation of MAPK, although in a cell type-specific manner. Moreover, the differences between the activities of hSef-a and hSef-b suggest that hSef isoforms can control signal specificity and subsequent cell fate by utilizing different mechanisms to modulate RTK signaling. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Note:
Related Files :
animal cell
Animals
apoptosis
Cell Proliferation
enzymes
HeLa cells
mice
Receptor Protein-Tyrosine Kinases
sef a
עוד תגיות
תוכן קשור
More details
DOI :
10.1074/jbc.M607327200
Article number:
Affiliations:
Database:
סקופוס
Publication Type:
מאמר
;
.
Language:
אנגלית
Editors' remarks:
ID:
20916
Last updated date:
02/03/2022 17:27
Creation date:
16/04/2018 23:40
You may also be interested in
Scientific Publication
The human Sef-a isoform utilizes different mechanisms to regulate receptor tyrosine kinase signaling pathways and subsequent cell fate
281
Ziv, I., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Fuchs, Y., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Preger, E., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Shabtay, A., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel, Dept. of Cattle and Genetic Sciences, Institute of Animal Science, Agricultural Research Organization Newe-Ya'ar Research Center, Ramat Yishay 30095, Israel
Harduf, H., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel, Laboratory for Research in Reproductive Sciences, Dept. of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, Israel, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Zilpa, T., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Dym, N., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
Ron, D., Department of Biology, Technion Institute of Technology, Haifa 32000, Israel
The human Sef-a isoform utilizes different mechanisms to regulate receptor tyrosine kinase signaling pathways and subsequent cell fate
Negative feedback is among the key mechanisms for regulating receptor tyrosine kinase (RTK) signaling. Human Sef, a recently identified inhibitor of RTK signaling, encodes different isoforms, including a membrane spanning (hSef-a) and a cytosolic (hSef-b) isoform. Previously, we reported that hSef-b inhibited fibroblast proliferation and prevented the activation of mitogen-activated protein kinase (MAPK), without affecting protein kinase B/Akt or p38 MAPK. Conflicting results were reported concerning hSef-a inhibition of MAPK activation, and the effect of hSef-a on other RTK-induced signaling pathways is unknown. Here we show that, in fibroblasts, similar to hSef-b, ectopic expression of hSef-a inhibited fibroblast growth factor-induced cell proliferation. Unlike hSef-b, however, the growth arrest was mediated via a MAPK-independent mechanism, and was accompanied by elevated p38 MAPK phosphorylation and inhibition of protein kinase B/Akt. In addition, hSef-a, but not hSef-b, mediated apoptosis in fibroblast growth factor-stimulated cells. Chemical inhibitor of p38 MAPK abrogated the effect of hSef-a on apoptosis. In epithelial cells, ectopic expression of hSef-a inhibited the activation of MAPK, whereas downregulation of endogenous hSef-a significantly increased MAPK activation and accelerated growth factor-dependent cell proliferation. These results indicate that hSef-a is a multifunctional negative modulator of RTK signaling and clearly demonstrate that hSef-a can inhibit the activation of MAPK, although in a cell type-specific manner. Moreover, the differences between the activities of hSef-a and hSef-b suggest that hSef isoforms can control signal specificity and subsequent cell fate by utilizing different mechanisms to modulate RTK signaling. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Scientific Publication
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