Mutation of a Src phosphorylation site in the PDGF beta-receptor leads to increased PDGF-stimulated chemotaxis but decreased mitogenesis
Hansen, Klaus ; Johnell, Matilda ; Siegbahn, Agneta ; Rorsman, Charlotte ; Engström, Ulla ; Wernstedt, Christer ; Heldin, Carl-Henrik and Rönnstrand, Lars LU
(1996)
In EMBO Journal
15(19).
p.5299-5313
- Abstract
- Ligand induced activation of the beta-receptor for platelet-derived growth factor (PDGF) leads to activation of Src family tyrosine kinases. We have explored the possibility that the receptor itself is a substrate for Src. We show that Tyr934 in the kinase domain of the PDGF receptor is phosphorylated by Src. Cell lines expressing a beta-receptor mutant, in which Tyr934 was replaced with a phenyalanine residue, showed reduced mitogenic signaling in response to PDGF-BB. In contrast, the mutant receptor mediated increased signals for chemotaxis and actin reorganization. Whereas the motility responses of cells expressing wild-type beta-receptors were attenuated by inhibition of phosphatidylinositol 3'-kinase, those of cells expressing the... (More)
- Ligand induced activation of the beta-receptor for platelet-derived growth factor (PDGF) leads to activation of Src family tyrosine kinases. We have explored the possibility that the receptor itself is a substrate for Src. We show that Tyr934 in the kinase domain of the PDGF receptor is phosphorylated by Src. Cell lines expressing a beta-receptor mutant, in which Tyr934 was replaced with a phenyalanine residue, showed reduced mitogenic signaling in response to PDGF-BB. In contrast, the mutant receptor mediated increased signals for chemotaxis and actin reorganization. Whereas the motility responses of cells expressing wild-type beta-receptors were attenuated by inhibition of phosphatidylinositol 3'-kinase, those of cells expressing the mutant receptor were only slightly influenced. In contrast, PDGF-BB-induced chemotaxis of the cells with the mutant receptor was attenuated by inhibition of protein kinase C, whereas the chemotaxis of cells expressing the wild-type beta-receptor was less affected. Moreover, the PDGF-BB-stimulated tyrosine phosphorylation of phospholipase C-gamma was increased in the mutant receptor cells compared with wild-type receptor cells. In conclusion, the characteristics of the Y934F mutant suggest that the phosphorylation of Tyr934 by Src negatively modulates a signal transduction pathway leading to motility responses which involves phospholipase C-gamma, and shifts the response to increased mitogenicity. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1783961
- author
- Hansen, Klaus
; Johnell, Matilda
; Siegbahn, Agneta
; Rorsman, Charlotte
; Engström, Ulla
; Wernstedt, Christer
; Heldin, Carl-Henrik
and Rönnstrand, Lars
LU
- publishing date
- 1996
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Platelet-Derived Growth Factor/genetics/*metabolism Recombinant Fusion Proteins/metabolism Signal Transduction/physiology Type C Phospholipases/metabolism Tyrosine/metabolism src Homology Domains, Platelet-Derived Growth Factor beta Receptors, Actins/metabolism Amino Acid Sequence Cell Division Cell Line Chemotaxis/*physiology Chromones/pharmacology Enzyme Inhibitors/pharmacology Hela Cells Humans Isoenzymes/metabolism Kinetics Molecular Sequence Data Morpholines/pharmacology Mutation Peptides/chemical synthesis/metabolism Phosphatidylinositol 3-Kinases Phospholipase C gamma Phosphorylation/drug effects Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors Platelet-Derived Growth Factor/pharmacology Protein Binding Protein Kinase C/antagonists & inhibitors Proto-Oncogene Proteins pp60(c-src)/*metabolism Receptor
- in
- EMBO Journal
- volume
- 15
- issue
- 19
- pages
- 5299 - 5313
- publisher
- Oxford University Press
- ISSN
- 1460-2075
- language
- English
- LU publication?
- no
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
- id
- 9e9bf984-83bd-4ca7-9900-900de6c12a02 (old id 1783961)
- alternative location
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC452274/
- date added to LUP
- 2016-04-04 09:42:32
- date last changed
- 2019-05-22 02:18:24
@article{9e9bf984-83bd-4ca7-9900-900de6c12a02,
abstract = {{Ligand induced activation of the beta-receptor for platelet-derived growth factor (PDGF) leads to activation of Src family tyrosine kinases. We have explored the possibility that the receptor itself is a substrate for Src. We show that Tyr934 in the kinase domain of the PDGF receptor is phosphorylated by Src. Cell lines expressing a beta-receptor mutant, in which Tyr934 was replaced with a phenyalanine residue, showed reduced mitogenic signaling in response to PDGF-BB. In contrast, the mutant receptor mediated increased signals for chemotaxis and actin reorganization. Whereas the motility responses of cells expressing wild-type beta-receptors were attenuated by inhibition of phosphatidylinositol 3'-kinase, those of cells expressing the mutant receptor were only slightly influenced. In contrast, PDGF-BB-induced chemotaxis of the cells with the mutant receptor was attenuated by inhibition of protein kinase C, whereas the chemotaxis of cells expressing the wild-type beta-receptor was less affected. Moreover, the PDGF-BB-stimulated tyrosine phosphorylation of phospholipase C-gamma was increased in the mutant receptor cells compared with wild-type receptor cells. In conclusion, the characteristics of the Y934F mutant suggest that the phosphorylation of Tyr934 by Src negatively modulates a signal transduction pathway leading to motility responses which involves phospholipase C-gamma, and shifts the response to increased mitogenicity.}},
author = {{Hansen, Klaus and Johnell, Matilda and Siegbahn, Agneta and Rorsman, Charlotte and Engström, Ulla and Wernstedt, Christer and Heldin, Carl-Henrik and Rönnstrand, Lars}},
issn = {{1460-2075}},
keywords = {{Platelet-Derived Growth Factor/genetics/*metabolism
Recombinant Fusion Proteins/metabolism
Signal Transduction/physiology
Type C Phospholipases/metabolism
Tyrosine/metabolism
src Homology Domains; Platelet-Derived Growth Factor beta
Receptors; Actins/metabolism
Amino Acid Sequence
Cell Division
Cell Line
Chemotaxis/*physiology
Chromones/pharmacology
Enzyme Inhibitors/pharmacology
Hela Cells
Humans
Isoenzymes/metabolism
Kinetics
Molecular Sequence Data
Morpholines/pharmacology
Mutation
Peptides/chemical synthesis/metabolism
Phosphatidylinositol 3-Kinases
Phospholipase C gamma
Phosphorylation/drug effects
Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors
Platelet-Derived Growth Factor/pharmacology
Protein Binding
Protein Kinase C/antagonists & inhibitors
Proto-Oncogene Proteins pp60(c-src)/*metabolism
Receptor}},
language = {{eng}},
number = {{19}},
pages = {{5299--5313}},
publisher = {{Oxford University Press}},
series = {{EMBO Journal}},
title = {{Mutation of a Src phosphorylation site in the PDGF beta-receptor leads to increased PDGF-stimulated chemotaxis but decreased mitogenesis}},
url = {{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC452274/}},
volume = {{15}},
year = {{1996}},
}