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Structural and Functional Studies of Gas6

Stenhoff, Jonas LU (2007)
Abstract
The vitamin K-dependent and ubiquitously expressed 82 kDa glycoprotein product of the growth-arrest-specific-gene 6, Gas6, shows 44% sequence identity to the anticoagulant protein, protein S. Both proteins share further the same domain organization. A short loop region, 4 epidermal growth factor-like modules and an SHBG-like region follow the N-terminal Gla-domain, which confers membrane-binding capability. The Gas6 SHBG interacts with the receptor tyrosine kinases of the Tyro3 subfamily, Axl, Tyro3 and Mer. As a ligand to these receptors Gas6 is implicated in mediating for example growth, survival, migration, clearance of apoptotic cells and platelet response amplification.



The investigations described in this thesis... (More)
The vitamin K-dependent and ubiquitously expressed 82 kDa glycoprotein product of the growth-arrest-specific-gene 6, Gas6, shows 44% sequence identity to the anticoagulant protein, protein S. Both proteins share further the same domain organization. A short loop region, 4 epidermal growth factor-like modules and an SHBG-like region follow the N-terminal Gla-domain, which confers membrane-binding capability. The Gas6 SHBG interacts with the receptor tyrosine kinases of the Tyro3 subfamily, Axl, Tyro3 and Mer. As a ligand to these receptors Gas6 is implicated in mediating for example growth, survival, migration, clearance of apoptotic cells and platelet response amplification.



The investigations described in this thesis were aimed at shedding further light on the structure and function of these relatively recently discovered proteins. In study I, purified Gas6 was added to Gas6 deficient mouse cardiac fibroblasts, which responded by mitogenesis and increased survival. Employing a sensitive ELISA, in study II, Gas6 could be detected in human circulation (? 18 ng/mL) but not in human platelets. In study III it's shown that most of the Gas6 present in human circulation likely is complex bound to soluble extracellular domains of Axl. We further show that Gas6 ability to interact with its receptors relies on calcium. Study IV shows the high tendency of Gas6 to form multimers during purification. The multimers, which fail to interact with Axl, show slow association but high affinity binding towards bilayers containing phosphatidylserine. By contrast the monomers display fast association, low affinity binding and preference for bilayers containing phosphatidylethanolamine in addition to phosphatidylserine. (Less)
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author
supervisor
opponent
  • Associate Professor García de Frutos, Pablo, Institute for Biomedical Research of Barcelona-Spanish Council for Scientific Research, Barcelona, S
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Klinisk kemi, Clinical chemistry, EDTA, calcium, multimer, monomer, platelets, Mer, Axl, vitamin K, Gas6, human circulation, soluble receptor, Tyro3, receptor tyrosine kinases, growth factor
pages
157 pages
publisher
Department of Clinical Chemistry, Lund University
defense location
Medicinska klinikens aula, ingång 35, plan 1, Universitetssjukhuset MAS
defense date
2007-03-02 13:15:00
ISBN
978-91-85559-09-1
language
English
LU publication?
yes
additional info
Jonas Stenhoff, Björn Dahlbäck and Sassan Hafizi. 2004. Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts Biochem Biophys Res Commun, vol 319 pp 871-8. Department of Clinical Chemistry, Malmö University Hospital, Malmö, Sweden (manuscript)
Istvan Balogh, Sassan Hafizi, Jonas Stenhoff, Karin Hansson and Björn Dahlbäck. 2005. Analysis of Gas6 in Human Platelets and Plasma Arterioscler Thromb Vasc Biol, vol 25 pp 1280-6. Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Wallenberg Laboratory, University Hospital Malmo, Sweden.
Jonas Stenhoff, Carl Ekman, Sassan Hafizi and Björn Dahlbäck. . Demonstration of Complexes between the Vitamin K-dependent Protein Gas6 and the Ectodomain of Receptor Tyrosine Kinase Axl in Human Circulation pp 19. Department of laboratory medicine, Clinical Chemistry, Lund University, University Hospital. Malmö, SE-20502 MaLMÖ (manuscript)
Jonas Stenhoff, Sassan Hafizi and Björn Dahlbäck. . High Tendency of Gas6 to form multimers during purification procedures; implications for analysis of functional properties pp 26. Department of Laboratory Medicine, Clinical Chemistry, Lund University, University Hospital, Malmö, SE-20502 Malmö, Sweden (manuscript)
id
8df43a28-9670-4eb9-91b0-82ddab728f57 (old id 548113)
date added to LUP
2016-04-01 16:42:29
date last changed
2018-11-21 20:43:35
@phdthesis{8df43a28-9670-4eb9-91b0-82ddab728f57,
  abstract     = {{The vitamin K-dependent and ubiquitously expressed 82 kDa glycoprotein product of the growth-arrest-specific-gene 6, Gas6, shows 44% sequence identity to the anticoagulant protein, protein S. Both proteins share further the same domain organization. A short loop region, 4 epidermal growth factor-like modules and an SHBG-like region follow the N-terminal Gla-domain, which confers membrane-binding capability. The Gas6 SHBG interacts with the receptor tyrosine kinases of the Tyro3 subfamily, Axl, Tyro3 and Mer. As a ligand to these receptors Gas6 is implicated in mediating for example growth, survival, migration, clearance of apoptotic cells and platelet response amplification.<br/><br>
<br/><br>
The investigations described in this thesis were aimed at shedding further light on the structure and function of these relatively recently discovered proteins. In study I, purified Gas6 was added to Gas6 deficient mouse cardiac fibroblasts, which responded by mitogenesis and increased survival. Employing a sensitive ELISA, in study II, Gas6 could be detected in human circulation (? 18 ng/mL) but not in human platelets. In study III it's shown that most of the Gas6 present in human circulation likely is complex bound to soluble extracellular domains of Axl. We further show that Gas6 ability to interact with its receptors relies on calcium. Study IV shows the high tendency of Gas6 to form multimers during purification. The multimers, which fail to interact with Axl, show slow association but high affinity binding towards bilayers containing phosphatidylserine. By contrast the monomers display fast association, low affinity binding and preference for bilayers containing phosphatidylethanolamine in addition to phosphatidylserine.}},
  author       = {{Stenhoff, Jonas}},
  isbn         = {{978-91-85559-09-1}},
  keywords     = {{Klinisk kemi; Clinical chemistry; EDTA; calcium; multimer; monomer; platelets; Mer; Axl; vitamin K; Gas6; human circulation; soluble receptor; Tyro3; receptor tyrosine kinases; growth factor}},
  language     = {{eng}},
  publisher    = {{Department of Clinical Chemistry, Lund University}},
  school       = {{Lund University}},
  title        = {{Structural and Functional Studies of Gas6}},
  year         = {{2007}},
}