InteractiveFly: GeneBrief

phosphatidylserine receptor: Biological Overview | References


Gene name - phosphatidylserine receptor

Synonyms -

Cytological map position-94A6-94A6

Function - receptor

Keywords - apoptosis, JNK pathway

Symbol - PSR

FlyBase ID: FBgn0038948

Genetic map position - 3R: 18,186,498..18,188,255 [-]

Classification -JmjC domain

Cellular location - nuclear



NCBI links: Precomputed BLAST | EntrezGene
BIOLOGICAL OVERVIEW

Exposure of phosphatidylserine is a conserved feature of apoptotic cells and is thought to act as a signal for engulfment of the cell corpse. A putative receptor for phosphatidylserine (PSR) was previously identified in mammalian systems. This receptor is proposed to function in engulfment of apoptotic cells, although gene ablation of PSR has resulted in a variety of phenotypes. The role of the predicted Drosophila homolog of PSR (dPSR) in apoptotic cell engulfment was examined and no obvious role for dPSR in apoptotic cell engulfment by phagocytes was found in the embryo. In addition, dPSR is localized to the nucleus, inconsistent with a role in apoptotic cell recognition. However, it was surprisind to find that overexpression of dPSR protects from apoptosis, while loss of dPSR enhances apoptosis in the developing eye. The increased apoptosis is mediated by the head involution defective (Wrinkled) gene product. In addition, the data suggest that dPSR acts through the c-Jun-NH2 terminal kinase pathway to alter the sensitivity to cell death (Krieser, 2007).

Evidence against a role for PSR in engulfment also comes from two other knockout models and from data on the localization of the protein. One of the reported mouse knockouts showed no difference in engulfment of apoptotic cells by macrophages in the mutant, although PSR-/- macrophages were generally inhibited in their release of pro- and anti-inflammatory cytokines. In addition, fibroblast lines established from PSR-/- embryos showed no defect in apoptotic cell engulfment or in their response to apoptotic cells. Zebrafish lacking PSR accumulated dead cells, but were not definitively shown to have defects in apoptotic cell engulfment. Finally, localization data from the current work and from a number of labs strongly supports a nuclear localization for the protein. This is not consistent with a role for PSR as a surface receptor for the recognition for apoptotic cells, although PS could theoretically modulate the activity of this protein within the cell (Krieser, 2007).

The observations support a role for dPSR in cell survival. In zebrafish, reduction of PSR resulted in an increase in the number of apoptotic cells present during development. In particular, the brains of these fish were shrunken and had an increase in apoptotic cells. In two of the mouse knockout models an increase in apoptotic cells was detected. However, all three knockouts resulted in perinatal lethality, with defects in differentiation in a variety of tissues. It is speculated that defects in engulfment detected in some of the gene ablation models could reflect a role for PSR in the proper differentiation of macrophages. Increased apoptosis seen in the current studies and by others might also be due to defects in proper differentiation in the absence of PSR (Krieser, 2007).

What insight can be gained from these studies into the function of dPSR in differentiation and cell survival? Increased dPSR results in a cell survival phenotype that is suppressed by activation of the JNK pathway, while loss of dPSR results in apoptosis, activated by the cell death regulator Hid, a known target of JNK activation in apoptosis. Taken together, these data suggest that dPSR may normally act to suppress JNK activation of Hid-induced apoptosis (Krieser, 2007).

JNK activation is important for many processes in cells, including cell death, proliferation and differentiation. A role for JNK in apoptosis was found in many mammalian cell types. Data from mouse knockouts of JNK also suggest a role for JNK in proliferation and differentiation. In addition, JNK activation in dying cells is required for proliferative signals originating from apoptotic cells in Drosophila. Interestingly, defects in proliferation and differentiation of many tissues were observed in mice that lack PSR. Taken together with observations of increased cell death in dPSR mutant flies, these observations suggest that some of the phenotypes seen in mouse and fish models of PSR gene ablation might be due to inappropriate activation of the JNK pathway (Krieser, 2007).

Based on genetic assays, it is proposed that one function of dPSR is to suppress Hid activation. Flies that lack dPSR show increased apoptosis in the developing pupal eye, which is suppressed in the absence of hid, while overexpression of dPSR results in ectopic cell survival. Hid function is required for the death of the interommatidial cells in the pupal retina. The results also showed that expression of dPSR can inhibit death induced by the expression of Hid- or Grim in the eye, and that loss of dPSR enhances Rpr-, Hid- or Grim-induced death in the eye. Interestingly, loss of one copy of hid can also suppress cell death induced by Rpr or Hid expression in the eye. Therefore alterations of dPSR levels in the eye may be altering Hid activity to modify the Grim- and Rprinduced eye phenotypes (Krieser, 2007).

JNK activation has been shown to increase hid activity. However, Hid activity is also modulated by activation of the Ras/Erk pathway. Ras activation results in the survival of ectopic interommatidial cells, through the downregulation of Hid activity. Ectopic Ras activation also results in genital rotation defects, similar to those seen with dPSR overexpression. This suggests that PSR overexpression might activate the Ras/Erk pathway. Based on the current data, it is not clear whether dPSR might activate Ras and thus suppress JNK activity, whether dPSR could suppress JNK and thus activate Ras, or whether dPSR might act independently in an opposing manner on the JNK and Ras pathways (Krieser, 2007).

By examining the function of dPSR in the Drosophila system, new insight has been provided into the controversy regarding this protein. Although no evidence was found that this protein plays a role in engulfment, it is important in cell survival. This is consistent with phenotypes seen in gene ablation models in other organisms. Furthermore, dPSR affects the JNK pathway, and this may provide a clue as to its diverse functions in mammals (Krieser, 2007).


REFERENCES

Reference names in red indicate recommended papers.

Search PubMed for articles about Drosophila phosphatidylserine receptor

Krieser, R. J., et al. (2007). The Drosophila homolog of the putative phosphatidylserine receptor functions to inhibit apoptosis. Development 134(13): 2407-14. PubMed ID: 17522160


Biological Overview

date revised: 28 September 2007

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