Kodi Ravichandran

..This review covers the recent progress in the areas of find-me and eat-me signals and how these relate to prompt and immunologically silent clearance of apoptotic cells...

..This perspective discusses recent exciting progress, gaps in our understanding, and the conflicting issues that arise from the newly acquired knowledge...

..This Review focuses on these recent developments and attempts to highlight some of the important questions in this field...

..New observations suggest that corpse clearance is tightly linked to apoptosis and that dying cells use both recruitment and eat-me signals for phagocyte attraction and recognition...

..Given the apparently central role that Shc plays signaling via many receptors, delineating the precise mechanism(s) of Shc-mediated signaling may be critical to our understanding of the effects mediated through these receptors...

..Of the two potential Grb2 binding sites (Y239 and Y317), Y239 appears to play a greater role in recruiting Sos through Grb2. These studies have implications for Ras activation and mitogenic signaling during T cell activation...

..Thus, Shc, through its interaction with two different ligands, is able to accomplish both membrane localization and binding to the activated receptor via a single PTB domain...

..These data suggest that SHIPbeta, which is normally expressed in B cells along with SHIPalpha, functions comparably with SHIPalpha and that these two isoforms are not likely to be antagonistic in their function in vivo...

..An intact raft structure was required for BCR-induced tyrosine phosphorylation of PLCgamma2 and the induction of Ca(2+) flux. Taken together, these data provide a functional role for lipid rafts in BCR signaling...

..Taken together, these data suggest that Dock180/ELMO and CrkII act as two evolutionarily conserved signaling submodules that coordinately regulate engulfment...

..Taken together, these data suggest that CED-2/CrkII and CED-10/Rac are part of an evolutionarily conserved pathway in engulfment of apoptotic cells...

..These data suggest that HLA-A2 downmodulation may require certain threshold levels of active Nef. The differential timing of CD4 and HLA-A2 downmodulation may have implications for HIV pathogenesis and immune evasion...

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..Finally, we have also identified a previously undescribed biochemical complex containing Vps34, dynamin and Rab5(GDP), thus providing a mechanism for Rab5 recruitment to the nascent phagosome...

..This suggests that a machinery that is distinct from receptor-mediated endocytosis is used in phagosome maturation...

..Thus, BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells...

..These data also have implications for macrophage handling of contents derived from apoptotic versus necrotic cells in atherosclerotic lesions...

..Together these data suggest that ELMO1-mediated cytoskeletal changes may be coordinated with ERM protein crosslinking activity during dynamic cellular functions...

..Thus, Dock180 and ELMO function together as a bipartite GEF to optimally activate Rac on upstream stimulation to mediate the engulfment of apoptotic cells and cell migration...

..Thus, both Shc expression and its tyrosine phosphorylation play an essential and nonredundant role in thymic T cell development...

..These studies suggest that DOCK180 may associate with different ELMO proteins to form cell-type specific complexes and may have functions in both the nucleus and the cytoplasm...

..This finding suggests that Rac activation by the ELMO.Dock180 complex at discrete intracellular locations mediated by the N-terminal 330 amino acids of ELMO1 rather than generalized Rac activation plays a role in cell migration...

..However, the components upstream of ELMO and Dock180 during engulfment remain elusive...

..This steric-inhibition model may be a general mechanism for regulating multiple SH3-domain-containing Dock180 family members and may have implications for a variety of biological processes...

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..The binding of the ligand appears to reorganize this pocket through local folding events triggering a conformational switch between the free and the complex forms...

..These data reveal a new mode of action of PH domains and a novel, evolutionarily conserved mechanism by which a bipartite GEF can activate Rac...

..Once apoptotic cells are identified, their uptake by phagocytes further depends on the molecular machinery highly conserved from Caenorhabditis elegans to mammals...

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..In this issue, Kurant et al. (2008) describe a new phagocytic receptor, called six-microns-under (SIMU), that promotes engulfment of apoptotic neurons by glial cells in the developing nervous system of Drosophila...

..This work provides the first link between the cellular processes of ubiquitylation/proteasomal degradation and the ability to clear apoptotic cells efficiently...

..Together, these data suggest that ARNO and ARF6 coordinate with the Dock180/Elmo complex to promote Rac activation at the leading edge of migrating cells...

..These data suggest that the bipartite GEF, ELMO1 and Dock180, play an important role in promoting cancer cell invasion and could be potential therapeutic targets for the treatment of diffuse malignant gliomas...

..The recent molecular delineation of the phagocytic process and the identification of novel signaling proteins involved in engulfment have provided an exciting new platform for future studies into this biologically important process...

..Because PTB-domain-containing adaptor proteins influence endocytosis and trafficking of membrane proteins and cell migration [15, 16], our data support a model wherein PTB-domain-containing adaptor proteins regulate Arf family proteins...

..The data suggest that Src family kinase mediated tyrosine phosphorylation of ELMO1 might represent an important regulatory mechanism that controls signaling through the ELMO1/Crk/Dock180 pathway...

..Together, these data suggest a critical role for ShcA in neural progenitor survival signaling and in regulating brain size...

..Taken together, these data reveal that GULP/LRP/ABCA1 represents a triad of molecules involved in engulfment and cellular lipid homeostasis...

..This work provides the first in vivo demonstration of the relative requirement of upstream adapters in controlling ERK activation during beta selection and suggests a dominant role for ShcA...

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..Since Shc has been linked to growth factor and cytokine signaling in lymphocytes and many other cell lineages, these studies would also have a broader importance for understanding signaling pathways affecting growth and differentiation. ..

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..In these mouse studies, we will determine the effect on engulfment due to the absence of GULP, or disrupted GULP function, and any potential effects on autoimmunity due to defective engulfment. ..

..Taken together, through these studies, we expect to gain a better molecular understanding of the fundamentally important process of clearing apoptotic cells and define the role of specific players during engulfment. ..

..The meeting is purposely held in alternative years with the Apoptosis meeting to encourage participation by all of those with an interest in cell death. ..

..Thus, we believe the outcome of these studies could have high degree of significance from a basic science perspective as well as human health. ..

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..A detailed molecular understanding of FcgammaRIIB-mediated inhibitory signaling may yield important clues to B cell activation and desensitization, and point to possible future therapeutic interventions in certain autoimmune states. ..

..Taken together, through these studies, we expect to gain a better molecular understanding of the fundamentally important process of clearing apoptotic cells and define the role of specific players during engulfment. ..