TY - JOUR
T1 - The Phosphatidylserine Receptor TIM-4 Does Not Mediate Direct Signaling
AU - Park, Daeho
AU - Hochreiter-Hufford, Amelia
AU - Ravichandran, Kodi S.
N1 - Funding Information:
We thank Vijay Kuchroo (Harvard Medical School, Boston) for generously providing the HA-TIM4 plasmid. We thank Tom Curran and Tae-Ju Park (Joseph Stokes Jr. Research Center, The Children's Hospital of Philadelphia) for generously providing the crk −/− MEF cells. We thank Matthew Hufford (University of Virginia, Charlottesville) for providing assistance with statistical analysis. We also thank members of the Ravichandran laboratory for help and discussions. This work was supported by grants from the National Institute of General Medical Sciences and the Strategic Program for Asthma Research.
PY - 2009/2/24
Y1 - 2009/2/24
N2 - Engulfment of apoptotic cells is an active process coordinated by receptors on phagocytes and ligands on apoptotic cells [1]. Phosphatidylserine (PtdSer) is a key ligand on apoptotic cells, and recently three PtdSer recognition receptors have been identified, namely, TIM-4, BAI1, and Stabilin-2 [1-6]. Whereas BAI1 is dependent on the ELMO1/Dock180/Rac signaling module, and Stablilin-2 appears to use the intracellular adaptor GULP [2, 3, 7], little is known about how TIM-4 transduces signals downstream of PtdSer recognition [8]. To test the role of known engulfment signaling pathways in TIM-4-mediated engulfment, we used a combination of dominant-negative mutants, knockdown of specific signaling proteins, and knockout cell lines. TIM-4 appears to be largely independent of the two known engulfment signaling pathways [7, 9-17], yet the TIM-4-mediated uptake is inhibited by cytoskeleton disrupting drugs. Remarkably, a version of TIM-4 lacking its cytoplasmic tail promoted corpse uptake via PtdSer recognition. Moreover, replacement of the transmembrane region of TIM-4 with a glycophosphatidylinositol anchor still promoted engulfment comparable to wild-type TIM-4. Thus, the transmembrane region and cytoplasmic tail of TIM-4 are dispensable for apoptotic cell engulfment, and we propose that TIM-4 is a PtdSer tethering receptor without any direct signaling of its own.
AB - Engulfment of apoptotic cells is an active process coordinated by receptors on phagocytes and ligands on apoptotic cells [1]. Phosphatidylserine (PtdSer) is a key ligand on apoptotic cells, and recently three PtdSer recognition receptors have been identified, namely, TIM-4, BAI1, and Stabilin-2 [1-6]. Whereas BAI1 is dependent on the ELMO1/Dock180/Rac signaling module, and Stablilin-2 appears to use the intracellular adaptor GULP [2, 3, 7], little is known about how TIM-4 transduces signals downstream of PtdSer recognition [8]. To test the role of known engulfment signaling pathways in TIM-4-mediated engulfment, we used a combination of dominant-negative mutants, knockdown of specific signaling proteins, and knockout cell lines. TIM-4 appears to be largely independent of the two known engulfment signaling pathways [7, 9-17], yet the TIM-4-mediated uptake is inhibited by cytoskeleton disrupting drugs. Remarkably, a version of TIM-4 lacking its cytoplasmic tail promoted corpse uptake via PtdSer recognition. Moreover, replacement of the transmembrane region of TIM-4 with a glycophosphatidylinositol anchor still promoted engulfment comparable to wild-type TIM-4. Thus, the transmembrane region and cytoplasmic tail of TIM-4 are dispensable for apoptotic cell engulfment, and we propose that TIM-4 is a PtdSer tethering receptor without any direct signaling of its own.
KW - CELLBIO
KW - SIGNALING
UR - https://www.scopus.com/pages/publications/60349123136
U2 - 10.1016/j.cub.2009.01.042
DO - 10.1016/j.cub.2009.01.042
M3 - Article
C2 - 19217291
AN - SCOPUS:60349123136
SN - 0960-9822
VL - 19
SP - 346
EP - 351
JO - Current Biology
JF - Current Biology
IS - 4
ER -