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|Coordinate||73,082,409 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||RAB27A, member RAS oncogene family|
|Synonym(s)||4933437C11Rik, 2210402C08Rik, 2410003M20Rik|
|Chromosomal Location||73,044,854-73,098,501 bp (+)|
|MGI Phenotype||Homozygotes have abnormal melanocyte development producing abnormal pigmentation and a gray coat color.|
|Amino Acid Change||Arginine changed to Stop codon|
|Institutional Source||Beutler Lab|
R54* in Ensembl: ENSMUSP00000034722 (fasta)
|Gene Model||not available|
|Phenotypic Category||immune system, MCMV susceptibility, pigmentation, skin/coat/nails|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Embryos, Sperm, gDNA|
|Last Updated||2016-05-13 3:09 PM by Peter Jurek|
Concrete was identified as a visible phenotype among ENU-induced G3 mutant mice. Homozygous concrete mice display a gray coat color and black eyes (Figure 1). Concrete mice are highly susceptible to mouse cytomegalovirus (MCMV) (MCMV Susceptibility and Resistance Screen), but resistant to Listeria monocytogenes. The mice also show a moderate bleeding diathesis, presumably due to platelet dysfunction. Natural killer (NK) cells from concrete mice fail to degranulate after antibody stimulation of NKp46 or Ly49H receptors, or after exposure to YAC-1 cells. Only 15-20% of concrete NK cells degranulate after PMA/ionomycin stimulation, compared with 80-90% of wild type cells. However, intracellular production of interferon (IFN)-γ is normal after PMA/ionomycin stimulation.
Concrete mice display normal type I interferon (IFN) responses to CpG DNA challenge in vivo.
|Nature of Mutation|
The concrete mutation was mapped to Chromosome 9, and corresponds to an A to T transversion at position 329 of the Rab27a transcript, in exon 3 of 6 total exons.
The mutated nucleotide is indicated in red lettering, and creates a premature stop codon at codon 54 (normally an arginine) deleting 167 amino acids from the C-terminus of the protein.
Rab proteins are low molecular weight GTPases that function in membrane trafficking and vesicular fusion and targeting. The presence of five sequence motifs designated Rab family motif (RabF) 1-5 distinguishes Rabs from other small GTPases (4). In addition, four regions designated Rab subfamily motif (RabSF) 1-4 share high amino acid sequence identity among Rabs of the same subfamily. Rab27a is a 221 amino acid protein that together with Rab27b forms the Rab27 subfamily. Rab27a and Rab27b are 70% identical overall, and 100%, 72%, 84%, and 76% identical, respectively, in their RabSF1, RabSF2, RabSF3, and RabSF4 motifs (4). Transgenic expression of Rab27b can compensate for the lack of Rab27a to restore normal coat color in Rab27aash mice (5) (See Background).
The crystal structures of Rab27a or Rab27b bound to a GTP analogue and either the R27BD of Slp2 or melanophilin, respectively, reveal that Rab27a exhibits a typical monomeric small GTPase globular fold consisting of five α helices surrounding six β strands (Figure 4) (14;15). Small GTPases contain a so-called “switch region” composed of switch I, interswitch, and switch II regions that changes conformation as a GTPase switches between the GTP- and GDP-bound states. RabF motifs are found clustered in the switch region of Rabs, with RabF1 in switch I and RabF2-5 in switch II (4). The SHD1 of the R27BDs of Slp2 and melanophilin form similar α helical structures that bind to residues in the interswitch and switch II regions of Rab27a. These residues belong to RabF1-4, RabSF1, RabSF3, and RabSF4 on the surface of Rab27a. In addition, three invariant hydrophobic aromatic amino acids from the switch region of Rab27a are essential for effector recognition (F46, W73, and F88). Residues outside of the Rab27a switch and interswitch regions make further contacts with the SHD2 located at the C-terminus of the R27BD. A sequence in SHD2 ([S/T][G/L]XW[F/Y][F/Y]) is thought to provide effectors with specificity for Rab27a/b.
The concrete mutation results in the conversion of the codon for arginine 54 to a stop codon. It likely results in a protein-null animal, or if any protein is expressed, a non-functional product, as the premature stop codon occurs early in the coding sequence (amino acid 54 of 221).
Northern blot analysis detects three Rab27a transcripts of distinct size, most likely due to differing lengths of 3’ untranslated region (7;16). In humans, RAB27A transcripts are found in most tissues, including spleen, thymus, prostate, testis, ovary, small intestine, colon, heart, placenta, lung, liver, muscle, kidney and pancreas, as well as in several tumor cell lines (leukemia, melanoma and HeLa cells) (7). Brain tissue is devoid of RAB27A expression. Leukocytes, platelets and melanocytes all express RAB27A (7). In mice, Rab27a expression has been analyzed by immunoblotting and found in eye, heart, intestine, lung, pancreas and spleen (17). Subcellularly, Rab27a is present on endosomes and lysosomes, and on a variety of lysosome-related and secretory organelles, including melanocytes in melanosomes (18) and lytic granules in cytotoxic T lymphocytes (CTLs) and NK cells (10).
More than 60 Rab GTPase proteins are expressed in mammalian cells, where they control distinct steps in intracellular transport. Four essential steps are recognized in the mechanism underlying membrane traffic [reviewed in (19;20)]. First, cargo is selected and a vesicular or tubular transport intermediate is formed. These intermediates are then delivered to their target membrane, often using molecular motors to move them along microtubules or actin filaments. Tethering/docking brings the intermediate and target membranes close together, and finally fusion of the two membranes mediated by soluble NSF attachment protein receptor (SNARE) proteins releases the cargo. Specificity at each step is necessary to maintain appropriate compartmentalization and cargo movement through the cell, and Rabs, ubiquitously expressed and associated with distinct intracellular compartments, are critical regulators of such specificity at each step of the trafficking process.
Eleven organelle-specific Rab27 effector proteins have so far been identified (Table 1).
Table 1. Rab27 effectors
First cloned as ram p25 from a rat megakaryocyte library in 1990 (7), Rab27a regulates the exocytosis of lysosome related organelles from CTLs, melanocytes, platelets, and endothelial cells, as well as the secretion of non-lysosome organelles from several other cell types including insulin-containing secretory granules of pancreatic β cells (26-28), and secretory granules of PC12 and chromaffin cells (43). Mutation of Rab27a results in the mouse phenotype ashen (ash), in which mice have a light coat color due to defects in pigment granule transport (44). Melanins, the pigments for skin, hair and eyes, are synthesized in melanosomes, which are then transported along microtubule and actin filaments to the ends of melanocyte dendrites and exported to neighboring keratinocytes (Figure 6). In Rab27aash mice, melanosomes are synthesized normally, but cluster in the perinuclear region, resulting in uneven and impaired release of melanin (18). The dilute (d) and leaden (ln) mice, which also have a light coat color, exhibit exactly the same cellular phenotype as Rab27aash mice (45;46), and further study of these three mutants revealed that their encoded protein products form a tripartite complex with Rab27a that regulates the microtubule to actin filament transfer of melanosomes, a crucial step leading to melanosome exocytosis (29-31;47;48). Dilute encodes the actin-based motor protein myosin Va (Myo5a) (49) (mutated in new gray, nut, silver decerebrate, and silver decerebrate 2) and leaden encodes the Rab27 effector melanophilin (Mlph, also called Slac2-a; mutated in koala) (50).
Once transported to the tips of dendrites, melanosomes must be captured there, docked, and released to adjacent keratinocytes. Rab27a and its effectors participate in the docking of melanosomes, as well as secretory vesicles in other cell types, to the plasma membrane using a general mechanism in which Rab27 effectors serve as adapter molecules that bridge the Rab27·vesicle complex and plasma membrane binding proteins or membrane components themselves [(60) and references therein]. Studies of Slp2, Slp4-a, and rabphilin suggest that they do so using their R27BDs to bind Rab27a, and another domain, a linker or tandem C2 domains with specificity for distinct plasma membrane molecules, to link to the cell membrane. In the case of melanosomes, Slp2 has been demonstrated to tether melanosomes to the plasma membrane of cultured skin melanocytes by binding to Rab27a and phosphatidylserine in the lipid bilayer (32). However, Slp2-deficient mice display no pigmentation defects, suggesting that other Rab27a effector proteins compensate for its loss (61). Instead, Slp2 is required for mucus granule docking and secretion in gastric surface mucous cells.
The diluted coat color phenotype of Rab27aash, Myo5ad and Mlphln mice can be rescued by the semi-dominant dilute suppressor (dsu) locus (62;63), which bears a mutation in the gene encoding melanoregulin (Mreg) (64). Mregdsu suppresses the coat color defect, but not the neurological or lethal effects of Myo5a-null alleles [i.e. dilute lethal (Myo5ad-l) and Myo5ad-l20J] (63;65), which must also affect the production of an alternatively spliced neuronal isoform of Myo5a (66). [On the other hand, Myo5ad (also called dilute viral, Myo5ad-v) contains a retroviral intronic insertion that disrupts the melanocyte-specific but not the neuronal-specific transcript (65;66).] Mregdsu does not suppress the diluted coat color of 14 other mutants which have mechanistically different causes for pigmentation defects, although it does suppress the ruby eye color of ruby-eye and ruby-eye-2 mice (67) (see records for stamper-coat, toffee, and dorian gray). The dsu locus has been demonstrated to function cell-autonomously in melanocytes; its protein product is not diffusible (68). Mregdsu modulates hair pigment through a myosin Va-independent pathway, as demonstrated by its inability to restore proper melanosome transport/localization in both Myo5ad/d and Myo5a-null melanocytes (64). Instead, Mregdsu alters the incorporation of pigment into hair, decreasing the normal spacing between bands of pigment in the hair. Mreg is a 214 amino acid vertebrate protein with no similarity to known motor proteins or transcription factors, and lacks any known functional domains. Thus, the mechanism by which it regulates pigment incorporation into hair is yet unknown. Recently, Mreg was shown to interact with peripherin-2, a tetraspanin protein regulating the formation of disk membranes, specialized organelles of photoreceptor rod cells (69).
In humans, mutations in RAB27A cause Griscelli syndrome type II, which is characterized by partial albinism and hemophagocytic syndrome (70) (OMIM #607624). The underlying mechanisms resulting in pigmentary dilution in humans are the same as those in mice, discussed above. Hemophagocytic syndrome (also called hemophagocytic lymphohistiocytosis, HLH) is characterized by polyclonal CD8 T cell and macrophage activation and infiltration of multiple organs, leading to death unless treated by bone marrow transplant (71). In Rab27aash mice, lytic granules of CTLs and natural killer (NK) cells are blocked at a late secretory step, successfully polarizing towards the immunological synapse (a microtubule-dependent step) but failing to fuse and release their contents (10;42). Interestingly, the Rab27a/melanophilin/myosin Va complex-dependent mechanism underlying melanosome secretion is not utilized during lytic granule secretion, as demonstrated by the normal cytolytic activity of CTLs and NK cells in Myo5ad mice (40), and normal immune function of myosin Va- and melanophilin-deficient patients (72;73). Furthermore, the perinuclear clusters of Rab27aash melanosomes are cytologically distinct from the membrane-proximal polarized lytic granules of Rab27aash CTLs. These findings suggest that Rab27a interacts with a different set of molecular partners to transport lytic granules of CTLs close to the immunological synapse than those utilized to transport melanosomes.
The secretory defect observed in Rab27a-deficient human and mouse CTLs is similar to that seen in human FHL3 (familial hemophagocytic lymphohistiocytosis 3; OMIM #608898) cells and mouse jinx cells, which harbor mutations in Munc13-4 (also called Unc13d) (74;75), a putative Rab27a binding partner in CTLs and NK cells (40;41). In FHL3 CTLs, lytic granules dock at the immunological synapse, but fail to fuse with the membrane, indicating a block in priming granules to fusion competence (75). In contrast, in Rab27aash CTLs, granules polarize and cluster near the membrane, but do not actually dock. Unc13d and Rab27a can be coimmunoprecipitated from platelets, CTLs and mast cells, and overexpression of Unc13d enhances degranulation of secretory lysosomes from mast cells and can rescue the dominant negative effect of an unprenylated activated Rab27a mutant on secretion from platelets (40;41). These data suggest that Unc13d functions as an effector of Rab27a during regulated exocytosis, although Rab27a and probably another effector are also required for the transport of granules close to the plasma membrane, an earlier step in the process of secretion. Recent data also demonstrate a Rab27a-independent function of Unc13d, in which Unc13d promotes the maturation of lytic granules by eliciting the fusion of recycling endosomes with late endosomes, and in turn, these vesicles with cytotoxic perforin/granzyme-containing vesicles (76).
The concrete mutation appears to result in a functionally null animal, as no Rab27a protein is detected in cells from these mice (1). Study of concrete mice supports previous work suggesting that neutrophil function is impaired in Griscelli syndrome patients. Abnormal bactericidal activity or phagocytic ability was observed in the neutrophils of some patients (2;3). Concrete mice display impaired secretion of azurophilic granules, lysosome-related organelles that contain MPO, defensins and other antimicrobial peptides, which can be released into phagosomes or extracellularly in order to kill invading bacteria. Interestingly, Rab27a localizes on only a small subset of MPO-containing granules, suggesting that this population of neutrophil granules is heterogeneous in its content of exocytic machinery. The Rab27a-containing granules are postulated to be available for release, while those lacking Rab27a may be non-releasable (1). This hypothesis is consistent with the observation that only a minor subpopulation of azurophilic granules is exocytosed (77). The mechanism of Rab27a-mediated azurophilic granule release involves the effector JFC1/Slp1, which can be co-immunoprecipitated with Rab27a from granulocytes and colocalizes with Rab27a at the surface of MPO-containing granules (1;36).
Lysosome-phagosome fusion is considered as a type of intracellular secretion, and azurophilic granules predominantly release their contents into phagosomes during bacterial engulfment. Notably, neither Rab27a nor JFC1/Slp1 are part of azurophilic granules that fuse with phagosomes during phagocytosis of a labeled substrate, and Rab27a-deficient neutrophils both efficiently phagocytose substrate and deliver MPO to phagosomes (1). These results suggest that Rab27a mediates the fusion of azurophilic granules with the plasma membrane, and that these Rab27a-containing granules are distinct from those that fuse with phagosomes.
Concrete mice are resistant to Listeria monocytogenes infections, a somewhat surprising finding since elimination of Listeria relies on neutrophil function. However, neutrophils may retain relatively normal function in concrete animals, as both phagosome loading and phagocytosis itself are normal in mutants. Concrete mice are highly susceptible to MCMV, and accordingly, NK cell degranulation is severely impaired.
|Primers||Primers cannot be located by automatic search.|
Concrete genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition. The same primers are used for PCR amplification and for sequencing.
Con(F): 5’-TTCGGGACTCAATTCTCTTGA -3’
1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40X
6) 72°C 10:00
7) 4°C ∞
The following sequence of 336 nucleotides (from Genbank genomic region NC_000075 for linear DNA sequence of Rab27α) is amplified:
37418 ttc gggactcaat tctcttgaga
37441 agtctaaatg ctttgagatt ttgtgctgaa tcgaaagtca agaagagccc gctggtctca
37501 gaatttccct tggcttatct ttgctttgct gttttaggtg tacagagcca atgggccaga
37561 tggagctgtg ggccgaggcc agagaatcca cctgcagtta tgggacacgg cggggcagga
37621 gaggtatgtc tccccagtct gtccacactg acctgggcag gagaggtgtg tctcccccag
37681 tctattcaca ctgacctggc caggcaaagg cagccaactg gctcatctgc acctggtaag
37741 atgagctgcc aga
Primer binding sites are underlined; the mutated A is shown in red text.
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10. Stinchcombe, J. C., Barral, D. C., Mules, E. H., Booth, S., Hume, A. N., Machesky, L. M., Seabra, M. C., and Griffiths, G. M. (2001) Rab27a is required for regulated secretion in cytotoxic T lymphocytes, J Cell Biol. 152, 825-834.11. Detter, J. C., Zhang, Q., Mules, E. H., Novak, E. K., Mishra, V. S., Li, W., McMurtrie, E. B., Tchernev, V. T., Wallace, M. R., Seabra, M. C., Swank, R. T., and Kingsmore, S. F. (2000) Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis, Proc. Natl. Acad. Sci. U. S. A 97, 4144-4149.
12. Fukuda, M. (2005) Versatile role of Rab27 in membrane trafficking: focus on the Rab27 effector families, J Biochem. (Tokyo) 137, 9-16.
13. Fukuda, M. (2002) Synaptotagmin-Like Protein (Slp) Homology Domain 1 of Slac2-a/melanophilin is a Critical Determinant of GTP-Dependent Specific Binding to Rab27A. J. Biol. Chem. 277, 40118-40124.
14. Chavas, L. M., Ihara, K., Kawasaki, M., Torii, S., Uejima, T., Kato, R., Izumi, T., and Wakatsuki, S. (2008) Elucidation of Rab27 Recruitment by its Effectors: Structure of Rab27a Bound to Exophilin4/Slp2-a. Structure. 16, 1468-1477.
15. Kukimoto-Niino, M., Sakamoto, A., Kanno, E., Hanawa-Suetsugu, K., Terada, T., Shirouzu, M., Fukuda, M., and Yokoyama, S. (2008) Structural Basis for the Exclusive Specificity of Slac2-a/melanophilin for the Rab27 GTPases. Structure. 16, 1478-1490.16. Tolmachova, T., Ramalho, J. S., Anant, J. S., Schultz, R. A., Huxley, C. M., and Seabra, M. C. (1999) Cloning, mapping and characterization of the human RAB27A gene, Gene 239, 109-116.
17. Seabra, M. C., Ho, Y. K., and Anant, J. S. (1995) Deficient geranylgeranylation of Ram/Rab27 in choroideremia, J Biol. Chem. 270, 24420-24427.
18. Hume, A. N., Collinson, L. M., Rapak, A., Gomes, A. Q., Hopkins, C. R., and Seabra, M. C. (2001) Rab27a regulates the peripheral distribution of melanosomes in melanocytes, J Cell Biol. 152, 795-808.
19. Grosshans, B. L., Ortiz, D., and Novick, P. (2006) Rabs and their effectors: achieving specificity in membrane traffic, Proc. Natl. Acad. Sci. U. S. A 103, 11821-11827.
20. Zerial, M. and McBride, H. (2001) Rab proteins as membrane organizers, Nat. Rev. Mol. Cell Biol. 2, 107-117.
21. Anant, J. S., Desnoyers, L., Machius, M., Demeler, B., Hansen, J. C., Westover, K. D., Deisenhofer, J., and Seabra, M. C. (1998) Mechanism of Rab Geranylgeranylation: Formation of the Catalytic Ternary Complex. Biochemistry. 37, 12559-12568.
22. Andres, D. A., Seabra, M. C., Brown, M. S., Armstrong, S. A., Smeland, T. E., Cremers, F. P., and Goldstein, J. L. (1993) CDNA Cloning of Component A of Rab Geranylgeranyl Transferase and Demonstration of its Role as a Rab Escort Protein. Cell. 73, 1091-1099.
23. Alexandrov, K., Horiuchi, H., Steele-Mortimer, O., Seabra, M. C., and Zerial, M. (1994) Rab Escort Protein-1 is a Multifunctional Protein that Accompanies Newly Prenylated Rab Proteins to their Target Membranes. EMBO J. 13, 5262-5273.
24. Rak, A., Pylypenko, O., Niculae, A., Pyatkov, K., Goody, R. S., and Alexandrov, K. (2004) Structure of the Rab7:REP-1 Complex: Insights into the Mechanism of Rab Prenylation and Choroideremia Disease. Cell. 117, 749-760.
25. Fukuda, M., Kanno, E., and Yamamoto, A. (2004) Rabphilin and Noc2 are Recruited to Dense-Core Vesicles through Specific Interaction with Rab27A in PC12 Cells. J. Biol. Chem. 279, 13065-13075.
26. Waselle, L., Coppola, T., Fukuda, M., Iezzi, M., El-Amraoui, A., Petit, C., and Regazzi, R. (2003) Involvement of the Rab27 binding protein Slac2c/MyRIP in insulin exocytosis, Mol. Biol. Cell 14, 4103-4113.27. Yi, Z., Yokota, H., Torii, S., Aoki, T., Hosaka, M., Zhao, S., Takata, K., Takeuchi, T., and Izumi, T. (2002) The Rab27a/granuphilin complex regulates the exocytosis of insulin-containing dense-core granules, Mol. Cell Biol. 22, 1858-1867.
28. Torii, S., Zhao, S., Yi, Z., Takeuchi, T., and Izumi, T. (2002) Granuphilin Modulates the Exocytosis of Secretory Granules through Interaction with Syntaxin 1a. Mol. Cell. Biol. 22, 5518-5526.
29. Wu, X. S., Rao, K., Zhang, H., Wang, F., Sellers, J. R., Matesic, L. E., Copeland, N. G., Jenkins, N. A., and Hammer, J. A.,3rd. (2002) Identification of an Organelle Receptor for Myosin-Va. Nat. Cell Biol. 4, 271-278.
30. Fukuda, M., Kuroda, T. S., and Mikoshiba, K. (2002) Slac2-a/melanophilin, the missing link between Rab27 and myosin Va: implications of a tripartite protein complex for melanosome transport, J Biol. Chem. 277, 12432-12436.
31. Strom, M., Hume, A. N., Tarafder, A. K., Barkagianni, E., and Seabra, M. C. (2002) A family of Rab27-binding proteins. Melanophilin links Rab27a and myosin Va function in melanosome transport, J Biol. Chem. 277, 25423-25430.
32. Kuroda, T. S., and Fukuda, M. (2004) Rab27A-Binding Protein Slp2-a is Required for Peripheral Melanosome Distribution and Elongated Cell Shape in Melanocytes. Nat. Cell Biol. 6, 1195-1203.
33. Yu, M., Kasai, K., Nagashima, K., Torii, S., Yokota-Hashimoto, H., Okamoto, K., Takeuchi, T., Gomi, H., and Izumi, T. (2007) Exophilin4/Slp2-a Targets Glucagon Granules to the Plasma Membrane through Unique Ca2+-Inhibitory Phospholipid-Binding Activity of the C2A Domain. Mol. Biol. Cell. 18, 688-696.
34. Holt, O., Kanno, E., Bossi, G., Booth, S., Daniele, T., Santoro, A., Arico, M., Saegusa, C., Fukuda, M., and Griffiths, G. M. (2008) Slp1 and Slp2-a Localize to the Plasma Membrane of CTL and Contribute to Secretion from the Immunological Synapse. Traffic. 9, 446-457.
35. Ostrowski, M., Carmo, N. B., Krumeich, S., Fanget, I., Raposo, G., Savina, A., Moita, C. F., Schauer, K., Hume, A. N., Freitas, R. P., Goud, B., Benaroch, P., Hacohen, N., Fukuda, M., Desnos, C., Seabra, M. C., Darchen, F., Amigorena, S., Moita, L. F., and Thery, C. (2010) Rab27a and Rab27b Control Different Steps of the Exosome Secretion Pathway. Nat. Cell Biol. 12, 19-30; sup pp 1-13.
36. Brzezinska, A. A., Johnson, J. L., Munafo, D. B., Crozat, K., Beutler, B., Kiosses, W. B., Ellis, B. A., and Catz, S. D. (2008) The Rab27a Effectors JFC1/Slp1 and Munc13-4 Regulate Exocytosis of Neutrophil Granules. Traffic. 9, 2151-2164.
37. El-Amraoui, A., Schonn, J. S., Kussel-Andermann, P., Blanchard, S., Desnos, C., Henry, J. P., Wolfrum, U., Darchen, F., and Petit, C. (2002) MyRIP, a Novel Rab Effector, Enables Myosin VIIa Recruitment to Retinal Melanosomes. EMBO Rep. 3, 463-470.
38. Cheviet, S., Coppola, T., Haynes, L. P., Burgoyne, R. D., and Regazzi, R. (2004) The Rab-Binding Protein Noc2 is Associated with Insulin-Containing Secretory Granules and is Essential for Pancreatic Beta-Cell Exocytosis. Mol. Endocrinol. 18, 117-126.
39. Wood, S. M., Meeths, M., Chiang, S. C., Bechensteen, A. G., Boelens, J. J., Heilmann, C., Horiuchi, H., Rosthoj, S., Rutynowska, O., Winiarski, J., Stow, J. L., Nordenskjold, M., Henter, J. I., Ljunggren, H. G., and Bryceson, Y. T. (2009) Different NK Cell-Activating Receptors Preferentially Recruit Rab27a Or Munc13-4 to Perforin-Containing Granules for Cytotoxicity. Blood. 114, 4117-4127.
40. Neeft, M., Wieffer, M., de Jong, A. S., Negroiu, G., Metz, C. H., van, L. A., Griffith, J., Krijgsveld, J., Wulffraat, N., Koch, H., Heck, A. J., Brose, N., Kleijmeer, M., and van der, S. P. (2005) Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells, Mol. Biol. Cell 16, 731-741.
41. Shirakawa, R., Higashi, T., Tabuchi, A., Yoshioka, A., Nishioka, H., Fukuda, M., Kita, T., and Horiuchi, H. (2004) Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets, J Biol. Chem. 279, 10730-10737.
42. Haddad, E. K., Wu, X., Hammer, J. A., III, and Henkart, P. A. (2001) Defective granule exocytosis in Rab27a-deficient lymphocytes from Ashen mice, J Cell Biol. 152, 835-842.43. Desnos, C., Schonn, J. S., Huet, S., Tran, V. S., El-Amraoui, A., Raposo, G., Fanget, I., Chapuis, C., Menasche, G., de Saint, B. G., Petit, C., Cribier, S., Henry, J. P., and Darchen, F. (2003) Rab27A and its effector MyRIP link secretory granules to F-actin and control their motion towards release sites, J Cell Biol. 163, 559-570.
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|Science Writers||Eva Marie Y. Moresco|
|Illustrators||Diantha La Vine|
|Authors||Sophie Rutschmann, Celine Eidenschenk, Bruce Beutler|
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