Gas6 and protein S

Hafizi, Sassan; Dahlbäck, Björn

doi:10.1111/j.1742-4658.2006.05529.x

Cited by 311 publications

(150 citation statements)

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“…Both Gas6 and protein S are common ligands for the Tyro 3 RTK subfamily (Hafizi & Dahlback 2006a). It has been reported that phagocytic clearance of apoptotic cells by macrophages is mediated by Mer (Scott et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Each of the three members is composed of two N-terminal immunoglobulin-like domains and two fibronectin type III repeats in their extracellular regions. Two highly similar vitamin K-dependent proteins, Gas6 (product of growth arrestspecific gene 6) and protein S (a negative regulator of blood coagulation), are the biological ligands of the Tyro 3 RTK subfamily (Hafizi & Dahlback 2006a). These receptors and their ligands are widely expressed in cells of the immune, nervous, vascular, and reproductive systems.…”

Section: Introductionmentioning

confidence: 99%

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Gas6 and the Tyro 3 receptor tyrosine kinase subfamily regulate the phagocytic function of Sertoli cells

Xiong

Chen²,

Wang³

et al. 2008

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The apoptotic spermatogenic cells and residual bodies are phagocytosed and degraded by Sertoli cells during spermatogenesis. The mechanisms of this process are largely unknown. Here, we demonstrate that Gas6 and its receptors, the Tyro 3 subfamily of receptor tyrosine kinases (RTKs; Tyro 3, Axl, and Mer), regulate the phagocytic function of Sertoli cells. The phagocytic ability of Sertoli cells increased by five times in the presence of Gas6 in serum-free medium when compared with controls. The Sertoli cells lacking Mer showed a 35% reduction in phagocytosis of apoptotic spermatogenic cells when compared with wild-type (WT) controls, whereas the Sertoli cells lacking Tyro 3 or Axl exhibited phagocytic activity comparable with the controls. Notably, the Sertoli cells lacking all three members of the Tyro 3 RTK subfamily showed a dramatic decrease in phagocytic ability of 7.6-fold when compared with WT Sertoli cells. The deficiency in phagocytosis by the triple-mutant Sertoli cells was due to the deficit in binding of the Sertoli cells to apoptotic germ cells. These findings suggest that Mer is responsible for triggering phagocytosis of apoptotic spermatogenic cells by Sertoli cells and that Tyro 3, Axl, and Mer participate in recognizing and binding apoptotic germ cells by Sertoli cells in a redundant manner. Gas6 is a functional ligand of the Tyro 3 RTK subfamily in mediating phagocytic ability of Sertoli cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gas6 and the Tyro 3 receptor tyrosine kinase subfamily regulate the phagocytic function of Sertoli cells

Xiong

Chen²,

Wang³

et al. 2008

Reproduction

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“…Gas6, a paralog of protein S, promotes survival and proliferation of various types of cells by activating members of the Axl subfamily of receptor tyrosine kinases. These activities are abrogated when Gas6 is produced in the presence of warfarin, highlighting the indispensable nature of ␥-glutamyl carboxylation (19)(20)(21)(22). Additional evidence that Gla domains perform functions unrelated to hemostasis is provided by the recent identification of Gla domain proteins in ascidians, marine invertebrates that lack a blood coagulation cascade (23)(24)(25).…”

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confidence: 99%

Proline-rich Gla protein 2 is a cell-surface vitamin K-dependent protein that binds to the transcriptional coactivator Yes-associated protein

Kulman

Harris

Xie

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Proline-rich Gla protein 2 (PRGP2) is one of four known vertebrate transmembrane ␥-carboxyglutamic acid (Gla) proteins. Members of this protein family are broadly expressed in fetal and adult human tissues and share a common architecture consisting of a predicted propeptide and Gla domain, a single-pass transmembrane segment, and tandem Pro/Leu-Pro-Xaa-Tyr (PY) motifs near their C termini. Using a methodology developed for the regulated expression of enzymatically biotinylated proteins in mammalian cells, we demonstrate that PRGP2 undergoes ␥-glutamyl carboxylation in a manner that is both dependent upon the presence of a proteolytically cleavable propeptide and sensitive to warfarin, a vitamin K antagonist that is widely used as an antithrombotic agent. When expressed at physiologically relevant levels, the majority of PRGP2 is present in the ␥-glutamyl carboxylated, propeptide-cleaved (mature) form. We additionally demonstrate, by Western blotting and flow cytometry, that mature PRGP2 is predominantly located on the cell surface with the Gla domain exposed extracellularly. In a yeast two-hybrid screen that used the C-terminal cytoplasmic region of PRGP2 as bait, we identified the WW domain-containing transcriptional coactivator Yes-associated protein (YAP) as a binding partner for PRGP2. In GST pull-down experiments, both PRGP2 PY motifs and both YAP WW domains were essential for complex formation, as were residues proximal to the core sequence of the first PY motif. These findings suggest that PRGP2 may be involved in a signal transduction pathway, the impairment of which may be an unintended consequence of warfarin therapy.Gla domain ͉ warfarin ͉ WW domain

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“…The TAM RTK subfamily was identified most recently and contains three members -TYRO3, AXL, and MER (Hafizi & Dahlback 2006b). Two highly homologous vitamin K-dependent proteins, product of growth arrest-specific gene 6 (Gas6) and protein S (a negative regulator of blood coagulation) are the common ligands of TAM RTKs (Hafizi & Dahlback 2006a). Studies using gene knockout models have provided direct insights into the physiological functions of TAM RTKs (Lemke & Rothlin 2008).…”

Section: Introductionmentioning

confidence: 99%

Functions of TAM RTKs in regulating spermatogenesis and male fertility in mice

Chen¹,

Wang²,

Qi³

et al. 2009

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Mice lacking TYRO3, AXL and MER (TAM) receptor tyrosine kinases (RTKs) are male sterile. The mechanism of TAM RTKs in regulating male fertility remains unknown. In this study, we analyzed in more detail the testicular phenotype of TAM triple mutant (TAM K/K ) mice with an effort to understand the mechanism. We demonstrate that the three TAM RTKs cooperatively regulate male fertility, and MER appears to be more important than AXL and TYRO3. TAM K/K testes showed a progressive loss of germ cells from elongated spermatids to spermatogonia. Young adult TAM K/K mice exhibited oligo-astheno-teratozoospermia and various morphological malformations of sperm cells. As the mice aged, the germ cells were eventually depleted from the seminiferous tubules. Furthermore, we found that TAM K/K Sertoli cells have an impaired phagocytic activity and a large number of differentially expressed genes compared to wild-type controls. By contrast, the function of Leydig cells was not apparently affected by the mutation of TAM RTKs. Therefore, we conclude that the suboptimal function of Sertoli cells leads to the impaired spermatogenesis in TAM K/K mice. The results provide novel insight into the mechanism of TAM RTKs in regulating male fertility. Reproduction (2009) 138 655-666

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Gas6 and protein S

Cited by 311 publications

References 116 publications

Gas6 and the Tyro 3 receptor tyrosine kinase subfamily regulate the phagocytic function of Sertoli cells

Gas6 and the Tyro 3 receptor tyrosine kinase subfamily regulate the phagocytic function of Sertoli cells

Proline-rich Gla protein 2 is a cell-surface vitamin K-dependent protein that binds to the transcriptional coactivator Yes-associated protein

Functions of TAM RTKs in regulating spermatogenesis and male fertility in mice

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