Ced-12 Explained

Cell death abnormality gene 12
Organism:Caenorhabditis elegans
Taxid:6239
Symbol:CED-12
Entrezgene:172890
Homologene:56685
Refseqmrna:NM_060292.7
Refseqprotein:NP_492693.1
Uniprot:Q8STE5
Chromosome:I
Entrezchromosome:NC_003279.8
Genloc Start:10222261
Genloc End:10227627

CED-12 (ll eath Abnormality Protein-12) is a cytoplasmic, PH-domain containing adaptor protein found in Caenorhabditis elegans and Drosophila melanogaster. CED-12 is a homolog to the ELMO protein found in mammals. This protein is involved in Rac-GTPase activation, apoptotic cell phagocytosis, cell migration, and cytoskeletal rearrangements.[1] [2]

Discovery

The discovery of CED-12 was done using knockout experiments.[1] Its involvement in the apoptotic phagocytosis pathway was first noted when knocked-out ced-12 in C. elegans showed similar results in the apoptotic process to ced-5 and ced-2 knockouts.[3] This lead researchers to believe, and later confirm, that the protein products of ced-12 (CED-12), ced-5 (CED-5), and ced-2 (CED-2) all functioned as part of the same pathway.[3] [4]

Researchers also noted direct protein-protein interactions between CED-12 and CED-10 (C. elegans homolog for Rac1), a Rac-GTPase (energy-dependent protein found used for cytoskeletal rearrangements among other functions).[5] [6] CED-10 was inactive when CED-12 was knocked-out. Expression of CED-12 with CED-5 and CED-2 activated CED-10, which lead to the activation of apoptotic phagocytosis.[3]

Function

CED-12 is an adaptor protein (proteins involved in facilitating the formation of signalling complexes) that is translated once apoptosis has been triggered in a cell. Apoptosis, also known as programmed cell death, activates during development as well as in situations where a cell has received sufficient physical damage.[7] [8] Many of the contents within a cell are reactive with the environment outside of the cell and must be disposed of without causing any harm to the surrounding tissues. Apoptotic cells are removed from their external environment by neighbouring cells that recognize cell-surface markers located on the apoptotic cell membrane. Marker recognition leads to the engulfment of apoptotic cells by phagocytosis.[8] On a molecular level, recognition of the cell-surface markers leads to the translation of the CED-12 protein in the cytoplasm of the engulfing cell, which then gets localized to the cell membrane. CED-12 binds CED-2 (C. elegans homolog to CrkII in mammals), followed by CED-5 (C. elegans homolog for DOCK180 in mammals) and forms a ternary structure.[5] [9] Transmembrane CED-1 is an example of the cell-surface receptor on the engulfing cell. When receptors come in contact with cell surface markers on the apoptotic cell, a protein known as CED-6 (homolog for GULP in mammals) is expressed.[10] Both the CED-2/CED-5/CED-12 ternary structure and CED-6 function to activate an effector protein known as CED-10. CED-10 is a RAC-GTPase protein that is directly responsible for the rearrangement of the actin cytoskeleton that initiates phagocytosis.[5] [6] This process is regulated by two pathways. The first is by CED-6, which is an adaptor protein that is responsible for coordinating protein-protein interactions between CED-10 and actin.[11] The second pathway occurs when the CED-2/CED-5/CED-12 ternary structure form a GEF (guanine nucleotide exchange factor) with CED-10, which promotes the binding of a GTP energy molecule in order to activate the GTP-dependent CED-10.[5] [11]

CED-12 also functions in cell migration processes, which is regulated by the same interactions as the apoptotic phagocytosis pathway. It functions in distal tip cell migration in gonad development in C. elegans.[12] Distal tip cells are somatic cells located at the tip of developing gonadal arms, and are responsible for the elongation of the gonadal arm as well as controlling mitotic and meiotic cell division of gonadal cells throughout development and adulthood.[13] As C. elegans develops, the distal cells undergo a series of migrations in order to complete morphological changes, which define both gonad shape and size.[12] This process occurs when integrins on the surface of the distal tip cells meet chemoattractants located on the extracellular matrix.[12] The integrins form focal adhesions at the sites of the chemoattractants, which causes the localization of CED-5 to the adhesion points.[12] CED-12 and CED-2 form the GEF-trio with CED-5 and activate the CED-10 Rac-GTPase in order to rearrange the actin cytoskeleton and promote the forward propagation of the distal tip cells.[12] [14]

Gene and protein structure

The ced-12 gene codes for an 82kDa large protein, which spans 731 amino acids in length.[2] It is found on chromosome 2 on the L-arm in Drosophila, and on chromosome I in C. elegans.[1] The protein structure of CED-12 is separated based on its binding domains:

Interactions

CED-12 has been shown to interact with:[5] [11]

Notes and References

  1. Web site: Brody. Thomas . vanc . Ced-12. The Interactive Fly. November 11, 2015.
  2. Zhou Z, Caron E, Hartwieg E, Hall A, Horvitz HR . The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway . Developmental Cell . 1 . 4 . 477–89 . October 2001 . 11703939 . 10.1016/s1534-5807(01)00058-2 . free .
  3. Book: Pasqualini. Renata. Arap . vanc . Wadih. Protein Discovery Technologies. 2009. CRC Press. 978-1420014211. 175.
  4. Chung S, Gumienny TL, Hengartner MO, Driscoll M . A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans . Nature Cell Biology . 2 . 12 . 931–7 . December 2000 . 11146658 . 10.1038/35046585 . 743063 .
  5. Lettre G, Hengartner MO . Developmental apoptosis in C. elegans: a complex CEDnario . Nature Reviews. Molecular Cell Biology . 7 . 2 . 97–108 . February 2006 . 16493416 . 10.1038/nrm1836 . 15323587 .
  6. Raftopoulou M, Hall A . Cell migration: Rho GTPases lead the way . Developmental Biology . 265 . 1 . 23–32 . January 2004 . 14697350 . 10.1016/j.ydbio.2003.06.003 . free .
  7. Programmed cell death. WormBook: The Online Review of C. Elegans Biology. 2005-10-06. 18061982 . 2015-12-02. Conradt . B. . Xue . D. . 1–13 . 10.1895/wormbook.1.32.1 . 4781248 .
  8. Elmore S . Apoptosis: a review of programmed cell death . Toxicologic Pathology . 35 . 4 . 495–516 . June 2007 . 17562483 . 2117903 . 10.1080/01926230701320337 .
  9. Wang X, Wu YC, Fadok VA, Lee MC, Gengyo-Ando K, Cheng LC, Ledwich D, Hsu PK, Chen JY, Chou BK, Henson P, Mitani S, Xue D . 6 . Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12 . Science . 302 . 5650 . 1563–6 . November 2003 . 14645848 . 10.1126/science.1087641 . 2003Sci...302.1563W . 25672278 .
  10. Kinchen JM, Cabello J, Klingele D, Wong K, Feichtinger R, Schnabel H, Schnabel R, Hengartner MO . 6 . Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans . Nature . 434 . 7029 . 93–9 . March 2005 . 15744306 . 10.1038/nature03263 . 2005Natur.434...93K . 13399557 .
  11. Ravichandran KS, Lorenz U . Engulfment of apoptotic cells: signals for a good meal . Nature Reviews. Immunology . 7 . 12 . 964–74 . December 2007 . 18037898 . 10.1038/nri2214 . 10670430 .
  12. Wong MC, Schwarzbauer JE . Gonad morphogenesis and distal tip cell migration in the Caenorhabditis elegans hermaphrodite . Wiley Interdisciplinary Reviews. Developmental Biology . 1 . 4 . 519–31 . 2012 . 23559979 . 3614366 . 10.1002/wdev.45 .
  13. Web site: Reproductive System: The Somatic Gonad.
  14. Conradt B . Cell engulfment, no sooner ced than done . Developmental Cell . 1 . 4 . 445–7 . October 2001 . 11703934 . 10.1016/s1534-5807(01)00065-x . free .
  15. Weng Z, Rickles RJ, Feng S, Richard S, Shaw AS, Schreiber SL, Brugge JS . Structure-function analysis of SH3 domains: SH3 binding specificity altered by single amino acid substitutions . Molecular and Cellular Biology . 15 . 10 . 5627–34 . October 1995 . 7565714 . 230813 . 10.1128/mcb.15.10.5627 .
  16. Gumienny TL, Brugnera E, Tosello-Trampont AC, Kinchen JM, Haney LB, Nishiwaki K, Walk SF, Nemergut ME, Macara IG, Francis R, Schedl T, Qin Y, Van Aelst L, Hengartner MO, Ravichandran KS . 6 . CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration . Cell . 107 . 1 . 27–41 . October 2001 . 11595183 . 10.1016/s0092-8674(01)00520-7 . 15232864 . 2020-08-31 . 2021-09-22 . https://web.archive.org/web/20210922225900/https://www.zora.uzh.ch/id/eprint/952/1/Gumienny2001V.pdf . dead .