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Gene Review

ACKR2  -  atypical chemokine receptor 2

Homo sapiens

Synonyms: Atypical chemokine receptor 2, C-C chemokine receptor D6, CCBP2, CCR10, CCR9, ...
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Disease relevance of CCBP2


High impact information on CCBP2

  • Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization [5].
  • This cellular specificity correlated with the expression of the chemokine receptor CCR9 by a subset of MPP and common lymphoid progenitors but not hemopoietic stem cells [6].
  • CCR9 and CXCR6 have not been described previously on primary NK cells [7].
  • Thus, D6 has unique functional and structural features, which make it ideally adapted to act as a chemokine decoy and scavenger receptor, strategically located on lymphatic endothelium to dampen inflammation in tissues and draining lymph nodes [8].
  • D6 binds most inflammatory, but not homeostatic, CC chemokines and shuttles in a ligand-independent way from the plasma membrane to endocytic compartments where chemokines are targeted to degradation [8].

Chemical compound and disease context of CCBP2

  • In this study, we report that the D6/2 mutant and its double mutants containing second-site alanine substitutions at the five conserved amino acid residues (D251, D262, H331, E364, and E459) show increased POEP activity in serum-starved rat tumor hepatoma cells [9].

Biological context of CCBP2

  • An acidic region, but not the putative phosphorylation sites in the cytoplasmic tail of D6, is critical for receptor interaction with beta-arrestin and subsequent internalization [10].
  • Engagement of D6 by inflammatory CC chemokines elicited no calcium response nor chemotaxis, but resulted in efficient agonist internalization and degradation [11].
  • D6 usage may account for some previous observations of alternative receptor tropism for primary human cells [12].
  • Induction of Tax by Cd(2+) in JPX-9, a subline of Jurkat human T cell line carrying Tax under the control of metallothionein promoter, led to upregulation of CCR9 [13].
  • A luciferase reporter gene under the control of the CCR9 promoter was expressed by cotransfection of an expression vector for Tax or in Cd(2+)-treated JPX-9 cells [13].

Anatomical context of CCBP2

  • In lymph nodes, D6 immunoreactivity was present on the afferent lymphatics and also in subcapsular and medullary sinuses [14].
  • The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors [14].
  • By recognizing intact CCL22, but not its truncated variants, D6 expressed on lymphatic endothelial cells may regulate the traffic of CCR4-expressing cells, such as dendritic cells [15].
  • Peripheral blood cells and the ECs of blood vessels and high endothelial venules were consistently nonreactive with anti-D6 antibodies [14].
  • These results indicate that D6 acts as an inflammatory chemokine scavenging nonactivatory decoy receptors and suggest that in lymphatic vessels D6 may function as a gatekeeper for inflammatory CC chemokines, by clearing them and preventing excessive diffusion via afferent lymphatics to lymph nodes [11].

Associations of CCBP2 with chemical compounds

  • CSF contained similar proportions of CD4+ memory T cells expressing CLA, CCR4, integrin alpha4beta7 and CCR9 as paired blood samples [16].
  • We recently showed that activation of the CC chemokine 9 receptor (CCR9), a thymus-specific chemokine receptor, led to potent cFLIP(L)-independent resistance to cycloheximide-induced apoptosis and modest resistance to Fas-mediated apoptosis possibly via activation of multiple signaling components involving Akt and glycogen synthase kinase 3beta [17].
  • Our data revealed that constitutive expression of a mutant form of p67 (D6/2) in mammalian cells resulted in increased POEP activity, and this activity was partially inhibited when second-site alanine substitutions at the conserved amino acids D251, D262, E364, and E459 were introduced in the D6/2 mutant [18].

Physical interactions of CCBP2

  • The promiscuous D6 receptor binds several inflammatory CC chemokines and has been recently proposed to act as a chemokine-scavenging decoy receptor [15].

Regulatory relationships of CCBP2


Other interactions of CCBP2

  • These NH(2)-terminal truncated forms of CCL22 were not recognized by D6 [15].
  • Neither the native D6 nor mutants uncoupled from beta-arrestin activate any G-protein-mediated signaling pathways [10].
  • We have generated monoclonal antibodies to human D6 and showed D6 immunoreactivity on the ECs lining afferent lymphatics, confirmed as such by staining serial skin sections with antibodies against podoplanin, a known lymphatic EC marker [14].
  • Here, we show that D6, like CCR5, can rapidly internalize chemokines [20].
  • As an example, the migration of gamma delta T cells to the small intestine is guided by the chemokine receptor CCR9 and the local expression of the corresponding ligand CCL25 (also termed thymus-expressed chemokine, TECK) [21].

Analytical, diagnostic and therapeutic context of CCBP2

  • In parallel, in situ hybridization on skin with antisense D6 probes demonstrated the expression of D6 mRNA by lymphatic ECs [14].
  • Aim of this study was to investigate using immunohistochemistry techniques the interrelation between T immunoreactive cells and the expression of CCR10 and its ligand CCL27 in 59 cutaneous melanocytic lesions [22].
  • Thus, dissection of signaling components involved in the CCR9-mediated antiapoptosis could be a framework for cell survival mechanisms and may provide options for therapeutic interventions for neurdegenerative diseases or T cell malfunctioning [17].
  • RESULTS: The expression of cutaneous leukocyte antigen (CLA) and CC-chemokine receptor 4 (CCR4; associated with skin-homing) as well as the expression of integrin alpha4beta7 and CCR9 (associated with gut-homing) was analyzed on CD4+ memory T cells in CSF from individuals with non-inflammatory neurological diseases using flow cytometry [16].


  1. Selectively increased expression and functions of chemokine receptor CCR9 on CD4+ T cells from patients with T-cell lineage acute lymphocytic leukemia. Qiuping, Z., Qun, L., Chunsong, H., Xiaolian, Z., Baojun, H., Mingzhen, Y., Chengming, L., Jinshen, H., Qingping, G., Kejian, Z., Zhimin, S., Xuejun, Z., Junyan, L., Jinquan, T. Cancer Res. (2003) [Pubmed]
  2. Survey of chemokine receptor expression reveals frequent co-expression of skin-homing CCR4 and CCR10 in adult T-cell leukemia/lymphoma. Harasawa, H., Yamada, Y., Hieshima, K., Jin, Z., Nakayama, T., Yoshie, O., Shimizu, K., Hasegawa, H., Hayashi, T., Imaizumi, Y., Ikeda, S., Soda, H., Soda, H., Atogami, S., Takasaki, Y., Tsukasaki, K., Tomonaga, M., Murata, K., Sugahara, K., Tsuruda, K., Kamihira, S. Leuk. Lymphoma (2006) [Pubmed]
  3. Possible link between unique chemokine and homing receptor expression at diagnosis and relapse location in a patient with childhood T-ALL. Annels, N.E., Willemze, A.J., van der Velden, V.H., Faaij, C.M., van Wering, E., Sie-Go, D.M., Egeler, R.M., van Tol, M.J., Révész, T. Blood (2004) [Pubmed]
  4. Cloning and characterization of a novel promiscuous human beta-chemokine receptor D6. Nibbs, R.J., Wylie, S.M., Yang, J., Landau, N.R., Graham, G.J. J. Biol. Chem. (1997) [Pubmed]
  5. Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Liu, C., Saito, F., Liu, Z., Lei, Y., Uehara, S., Love, P., Lipp, M., Kondo, S., Manley, N., Takahama, Y. Blood (2006) [Pubmed]
  6. Selective thymus settling regulated by cytokine and chemokine receptors. Schwarz, B.A., Sambandam, A., Maillard, I., Harman, B.C., Love, P.E., Bhandoola, A. J. Immunol. (2007) [Pubmed]
  7. Evidence for NK cell subsets based on chemokine receptor expression. Berahovich, R.D., Lai, N.L., Wei, Z., Lanier, L.L., Schall, T.J. J. Immunol. (2006) [Pubmed]
  8. Silent chemoattractant receptors: D6 as a decoy and scavenger receptor for inflammatory CC chemokines. Locati, M., Torre, Y.M., Galliera, E., Bonecchi, R., Bodduluri, H., Vago, G., Vecchi, A., Mantovani, A. Cytokine Growth Factor Rev. (2005) [Pubmed]
  9. The binding between p67 and eukaryotic initiation factor 2 plays important roles in the protection of eIF2alpha from phosphorylation by kinases. Datta, B., Datta, R., Ghosh, A., Majumdar, A. Arch. Biochem. Biophys. (2006) [Pubmed]
  10. beta-Arrestin-dependent constitutive internalization of the human chemokine decoy receptor D6. Galliera, E., Jala, V.R., Trent, J.O., Bonecchi, R., Signorelli, P., Lefkowitz, R.J., Mantovani, A., Locati, M., Haribabu, B. J. Biol. Chem. (2004) [Pubmed]
  11. Cutting edge: scavenging of inflammatory CC chemokines by the promiscuous putatively silent chemokine receptor D6. Fra, A.M., Locati, M., Otero, K., Sironi, M., Signorelli, P., Massardi, M.L., Gobbi, M., Vecchi, A., Sozzani, S., Mantovani, A. J. Immunol. (2003) [Pubmed]
  12. The promiscuous CC chemokine receptor D6 is a functional coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and HIV-2 on astrocytes. Neil, S.J., Aasa-Chapman, M.M., Clapham, P.R., Nibbs, R.J., McKnight, A., Weiss, R.A. J. Virol. (2005) [Pubmed]
  13. Expression of CCR9 in HTLV-1(+) T cells and ATL cells expressing Tax. Nagakubo, D., Jin, Z., Hieshima, K., Nakayama, T., Shirakawa, A.K., Tanaka, Y., Hasegawa, H., Hayashi, T., Tsukasaki, K., Yamada, Y., Yoshie, O. Int. J. Cancer (2007) [Pubmed]
  14. The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. Nibbs, R.J., Kriehuber, E., Ponath, P.D., Parent, D., Qin, S., Campbell, J.D., Henderson, A., Kerjaschki, D., Maurer, D., Graham, G.J., Rot, A. Am. J. Pathol. (2001) [Pubmed]
  15. Differential recognition and scavenging of native and truncated macrophage-derived chemokine (macrophage-derived chemokine/CC chemokine ligand 22) by the D6 decoy receptor. Bonecchi, R., Locati, M., Galliera, E., Vulcano, M., Sironi, M., Fra, A.M., Gobbi, M., Vecchi, A., Sozzani, S., Haribabu, B., Van Damme, J., Mantovani, A. J. Immunol. (2004) [Pubmed]
  16. Human cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific trafficking determinants: relevance for immunotherapy. Kivisäkk, P., Tucky, B., Wei, T., Campbell, J.J., Ransohoff, R.M. BMC Immunol. (2006) [Pubmed]
  17. Role of the CC chemokine receptor 9/TECK interaction in apoptosis. Youn, B.S., Yu, K.Y., Oh, J., Lee, J., Lee, T.H., Broxmeyer, H.E. Apoptosis (2002) [Pubmed]
  18. Negative regulation of the protection of eIF2alpha phosphorylation activity by a unique acidic domain present at the N-terminus of p67. Datta, R., Tammali, R., Datta, B. Exp. Cell Res. (2003) [Pubmed]
  19. Circulating clonal CLA(+) and CD4(+) T cells in Sezary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymph node-homing chemokine receptor CCR7. Sokolowska-Wojdylo, M., Wenzel, J., Gaffal, E., Lenz, J., Speuser, P., Erdmann, S., Abuzahra, F., Bowman, E., Roszkiewicz, J., Bieber, T., Tüting, T. Br. J. Dermatol. (2005) [Pubmed]
  20. The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines. Weber, M., Blair, E., Simpson, C.V., O'Hara, M., Blackburn, P.E., Rot, A., Graham, G.J., Nibbs, R.J. Mol. Biol. Cell (2004) [Pubmed]
  21. Features and functions of gamma delta T lymphocytes: focus on chemokines and their receptors. Kabelitz, D., Wesch, D. Crit. Rev. Immunol. (2003) [Pubmed]
  22. Potential role of CCL27 and CCR10 expression in melanoma progression and immune escape. Simonetti, O., Goteri, G., Lucarini, G., Filosa, A., Pieramici, T., Rubini, C., Biagini, G., Offidani, A. Eur. J. Cancer (2006) [Pubmed]
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