ADAM17 (A Disintegrin And Metalloprotease-17): ADAM17, originally referred to as TNFalpha converting enzyme or TACE, mediates a proteolytic process referred to as ectodomain shedding. This process controls the density of cell surface receptors and adhesion molecules and causes the formation of various soluble factors. ADAM17 is expressed by most cells, including leukocytes. We have shown that ADAM17 in neutrophils and macrophages cleaves the adhesion molecule L-selectin, the pleiotropic cytokine TNFalpha, its two receptors TNF-RI, and TNF-RII, IL-6R, and the human IgG Fc receptor CD16. Down-regulating ADAM17 gene expression in leukocytes significantly attenuates local and systemic inflammation, yet bolsters neutrophil recruitment and bacterial clearance. These findings suggest that ADAM17 might be an important therapeutic target to down-regulate damaging inflammation, yet bolster neutrophil recruitment and bacterial clearance.
Li, Y., Brazzell, JL., Herrera, AH., Walcheck, B. 2006. ADAM17 mediates induced L-selectin shedding by mature neutrophils in vivo. Blood. 108:2275
Bell, J, Herrera, AH., Li, L., and Walcheck, B. 2007. Role of ADAM17 in the ectodomain shedding of TNF-alpha and its receptors by neutrophils and macrophages. J. Leukoc. Biol. 82:173.
Schaff, U., Mattila, P., Simon, S.I., and Walcheck, B. 2008. Neutrophil adhesion to E-selectin under shear promotes the redistribution and co-clustering of ADAM17 and its proteolytic substrate L-selectin. J. Leukoc. Biol. 83:99
Wang Y., Herrera, AH., Li, Y., and Walcheck, B. 2009. Regulation of mature ADAM17 by redox agents for L-selectin shedding. J. Immunol. 182:2449
Wang Y., Zhang, A., Herrera, AH., Ni, Z and Walcheck, B. 2010. ADAM17 activity and other mechanisms of soluble L-selectin production during death receptor-induced leukocyte apoptosis. J. Immunol. 184:4447
Long C., Wang Y., Herrera, AH., and Walcheck, B. 2010. In vivo role of leukocyte ADAM17 in inflammation induction during E. coli infection. J. Leukoc. Biol. 87:1097
Arndt PG, Strahan B, Wang Y, Long C, Horiuchi K, and Walcheck B. 2011. Leukocyte ADAM17 Regulates Acute Pulmonary Inflammation. PlosOne. 6(5): e19938
Wang Y., Robertson JD, Walcheck B. 2011 Different signaling pathways induce a disintegrin and metalloprotease-17 (ADAM17) in neutrophils during apoptosis and activation. J. Biol. Chem. 286: 38980
Long C, Hosseinkhani MR, Wang Y, Sriramarao P, and Walcheck B. 2012. ADAM17 regulates the adhesive properties of circulating neutrophils during E. coli infection. J. Leukoc. Biol. 92: 667
Wang Y, Wu J, Newton R, Bahaie NS, Long C, and Walcheck B. 2013. ADAM17 regulates the shedding of CD16b (FcγRIIIb) in human neutrophils. BBA - Mol. Cell Res. 1833:680
ADAM17 also regulates key activating receptors on natural killer (NK) cells, such as CD16a, that are important for binding to and killing cancer cells. Blocking ADAM17 activity or CD16a shedding may greatly bolster the ability of NK cells to kill cancer cells.
Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, Luo X, Cooley S, Verneris M, Walcheck B, Miller JS. 2013. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood. 121:3599
Wiernik A, Foley B, Zhang B, Verneris MR, Warlick E, Ross JA, Weisdorf DJ, Walcheck B, Vallera DA, and Miller J. 2013. Targeting CD33+ Acute Myeloid Leukemia with a bispecific killer cell engager (BiKE) and ADAM17 inhibition overcomes self inhibitory signals by potent activation through CD16 on NK cells. Clin Cancer Res. 19:3844
Jing Y, Ni Z, Wu J, Higgins L, Markowski TW, Kaufman DS, Walcheck B. 2015. Identification of an ADAM17 cleavage region in human CD16 (FcγRIII) and the engineering of a non-cleavable version of the receptor in NK cells. PLOS ONE. 10:e0121788
Skin migrating T cells: CHO-131 is a mouse anti-human monoclonal antibody (mAb) that specifically recognizes a glycan structure referred to as sLeX-modified, core 2 O-glycans (C2-O-sLeX). C2-O-sLeX decorates, in part, P-selectin glycoprotein ligand-1 (PSGL-1, CD162), which is an adhesion molecule expressed by leukocytes. PSGL-1 is recognized by the endothelial cell-expressed adhesion molecule P-selectin. This adhesion molecule interaction facilitates the attachment of leukocytes flowing in the blood to the vascular wall of blood vessels and their entry into sites of inflammation. We have demonstrated that CHO-131 stains a subset of human T cells (CHO-131+ T cells) that preferentially bind to P-selectin and accumulate at sites of inflammation in the skin, such as psoriasis lesions. These findings suggest that CHO-131+ T cells may play a key pathological role in certain chronic inflammatory diseases in the skin.
Ni, Z., Campbell J.J., Niehans, G., Walcheck, B. 2006. The mAb CHO-131 identifies a subset of cutaneous lymphocyte-associated antigen (CLA) T cells enriched in P-selectin-binding cells. J. Immunol. 177:4742
Ni, Z. and Walcheck, B. 2007. Varied levels of reactivity by different E-selectin/Fc constructs with cutaneous lymphocyte-associated antigen (CLA)+ CD4+ T cells. Immunol. Lett. 108:179
Ni, Z. and Walcheck, B. 2009. Cutaneous lymphocyte-associated antigen (CLA) T cells up-regulate P-selectin ligand expression upon their activation. Clinical Immunol. 133:25.
CHO-131+ tumor cells: Carcinoma is most common type of cancer occurring in humans. Carcinoma cells are derived from epithelial cells. The malignant transformation of normal cells can result in their expression of altered proteins and glycans, referred to as tumor antigens. Normal epithelial cells express little to none of the glycan C2-O-sLeX, specifically detected by the mAb CHO-131 (see above). We have shown, however, that certain carcinoma cells greatly up-regulate cell surface expression of C2-O-sLeX, which increases tumor cell binding to the endothelial cell-expressed adhesion molecule E-selectin. C2-O-sLeX expression is highly upregulated in colorectal adenocarcinomas and metastatic liver tumors compared to normal tissues, and is a potential early predictor of metastasis.
Walcheck, B., Leppanen, A., Cummings, RD., Knibbs, RN., Stoolman, LM., Alexander, SR., Mattila, PE., and McEver, RP. 2002. The monoclonal antibody CHO-131 binds to a core 2 O-glycan terminated with sialyl-Lewis x, which is a functional glycan ligand for P-selectin. Blood. 99:4063.
St. Hill, CA, Bullard, KM, and Walcheck B. 2005. Expression of the high-affinity selectin glycan ligand C2-O-sLeX by colon carcinoma cells. Cancer Lett. 217:105.
St Hill, C.A., Farooqui, M., Mitcheltree, G., Gulbahce, H.E., Jessurun, J., Cao, Q., Walcheck, B. 2009. The high affinity selectin glycan ligand C2-O-sLex and mRNA transcripts of the core 2 beta-1,6-N-acetylglusaminyltransferase (C2GnT1) gene are highly expressed in human colorectal adenocarcinomas. BMC Cancer 9:79.