Find-me signals

The correlation between the early stages of cell death and the removal of apoptotic cells was first studied in C. elegans. Mutants that could not carry out normal caspase-mediated apoptosis were used to demonstrate that cells in the beginning stages of death were still efficiently recognized and removed by phagocytes. This occurred because the engulfment machinery of the phagocytes was still functioning normally even though the apoptotic process in the dying cell was disrupted. A study done in 2003 showed the breast cancer cells release find me signals known as lysophosphatidylcholine. This research brought the concept of find-me signals to the fore front of cell clearance research and introduced the idea that dying cells release signals that flow throughout the body's tissues in order to alert and recruit monocytes to their location. == Chemicals that act as find-me signals ==

Known types of find-me signals include: • Lipids: • lysophosphatidylcholine (lysoPC) • sphingosine-1-phosphate (S1P) • Proteins and peptides: • fractalkine (CX3CL1) • interleukin-8 (IL-8) • complement components C3a and C5a • split tyrosyl tRNA synthetase (mini TyrRS) • dimerized ribosomal protein S19 (RP S19) • endothelial monocyte-activating polypeptide II (EMAP II) • Formyl peptides, especially N-formylmethionine-leucyl-phenylalanine, fMLP) • Nucleotides: adenosine triphosphate (ATP), adenosine diphosphate (ADP), uridine triphosphate (UTP) and uridine diphosphate (UDP). All of these molecules are linked to monocyte or macrophage recruitment towards dying cells. The role of LPC as a find-me signal has also not been characterized in vivo. It has also been suggested that S1P kinase 2 (SphK2) is a target of caspase 1, and that a cleaved fragment of SphK2 is what is released from dying cells into the surrounding extracellular space where it is transformed into S1P. All of the studies thus far characterizing S1P have been done in vitro, and the role or S1P in recruiting phagocytes to apoptotic cells in vivo has not been determined. A soluble fragment of fractalkine that is usually on the plasma membrane as an intercellular adhesion molecule is sent out as a 60 kDa fragment during apoptosis as a find me signal. CX3CL1 release is dependent upon caspase indirectly. Studies were able to show that the controlled release of the nucleotides ATP and UTP from cells in the beginning stages of apoptosis can potentially attract monocytes in vivo and in vitro. This has been observed in Jurkat cells (primary thymocytes), MCF-7 cells, and lung epithelial cells. Release is dependent upon caspase activity. Only a small amount of ATP is released during find me signaling, so it is unclear how the nucleotide avoids degradation by NTPases in order to establish a gradient used to signal clearing by monocytes. NTPases may serve as regulators in various tissues in order to control how far the nucleotide signal can travel. Research suggests that S19 is released during the late to final stages of apoptosis. This molecule has inflammatory properties, meaning it is capable of attracting and activating neutrophils. == In apoptosis ==

Background Humans turn over billions of cells as a part of normal bodily processes every day, which correlates with about 1 million cells being replaced per second. The ultimate goal of the body's intrinsic cell death mechanisms is to efficiently and asymptomatically clear dying cells. If the body's immune system, or more specifically phagocytes, fail to clear dying cells in the body, symptoms such as chronic inflammation, autoimmune disorders, and developmental abnormalities have been shown to occur. As long as the engulfment process is functioning and efficient, uncleared apoptotic cells go unnoticed in the body and do not cause any long-term symptoms. If this process is disrupted in any way, the accumulation of secondary necrotic cells in tissues of the body can occur. This is associated with autoimmune disorders, causing the immune system to attack self-antigens on the uncleared cells. Release from dying cells The main function of a find-me signal is to be released while a cell undergoing apoptosis is still intact in order to attract phagocytes to come and clear the dying cell before secondary necrosis can occur. They are released through a pannexin family channel known as PANX1. PANX1 is a four pass transmembrane protein that forms large pores in the plasma membrane of a cell, allowing molecules up to 1 kDa in size to pass through. The nucleotides are detected by P2Y2 on monocytes, which causes them to migrate to the location of the apoptotic cell. • The phagocytes interact with the dying cells through the presenting eat-me signals through specific eat-me signal receptors on the phagocytic cell. • The phagocyte will engulf the eat-me signal presenting cell through induced signaling of engulfment receptors and by the reorganization of the phagocytic cell's cytoskeleton. • The components of the dying cell are processed by the phagocytes within their lysosomes. == Non-apoptotic roles ==

Find me signals may also play a role in phagocytic activity of cell in the direct vicinity of cells undergoing apoptosis. In addition, they may also be able to enhance production of certain bridging molecules created by macrophages. ==See also==