CD222 at a glance

CD222 (CIMPR, cation-independent mannose 6-phosphate receptor; IGF2 receptor) is a ubiquitously expressed 250 kDa transmembrane lectin, which serves as one of the central protein transporters. No more than 10% of CD222 is present on the cell surface where it serves as a multifunctional receptor. Intracellular (major) fraction of CD222 is involved in transport of newly synthesized lysosomal enzymes modified by mannose 6-phosphate from Golgi apparatus to lysosomes. The cell surface CD222 binds and internalizes exogeneous mannose 6-phosphate-containing ligands.  CD222 thus constitutively recycles between cell surface and intracellulal vesicles.
CD222_schematic.jpgCD222 plays important roles in the organism. It is crucial for internalization and degradation of insulin-like growth factor 2, thus controling cell growth. It also complexes CD87 (urokinase-type plasminogen-activator receptor), plasminogen and latent TGF-beta, affecting their functions. CD222-mediated phagocytosis of plasminogen-coated apoptotic bodies is important for terminal phase of apoptosis. Impaired CD222 expression can indicate risk of tumor development. Last but not least CD222 serves as a receptor for heparanase and even for antigens of Listeria, and can mediate mannose 6-phosphate-dependent virus entry into various cells.
A soluble 205 kDa form of CD222 can be shedded from the cell surface into the blood, where it participates in the transport of mannose 6-phosphated proteins, and neutralizes plasminogen. This seems to be an important regulatory mechanism to inhibit angiogenesis and migration of cells. Higher levels of sCD222 have been detected in patients with liver diseases, as well as in case of breast cancer and multiple myeloma. Blocking of CD222 expression supports tumor progression.

Fig. 1: Schematic image of CD222 glycoprotein in its transmembrane form.

Taken together, CD222 research and detection seems to be one of promissing topics for near future.

CD222_AF647_FC.jpgThe mouse monoclonal antibody MEM-238 recognizes an extracellular (luminal) epitope between amino acids 192-697 of human CD222.
Workshop: HLDA VII; WS Code 70640
Applications: WB, FC(IC), FC
Available formats: 11-315-C100, 1B-315-C100, 1F-315-T100, 1P-315-T100, A6-315-T100, 1A-315-T100
The mouse monoclonal antibody MEM-240 recognizes an extracellular (luminal) epitope between amino acids 698-1262 of human CD222. 
Workshop: HLDA VII; WS Code 70641
Applications: WB, FC(IC), IP, FC
Available formats: 11-790-C100, 1P-790-T100
Fig. 2: Flow cytometry analysis of cell surface-expressed  CD222 in human peripheral blood using mouse monoclonal antibody MEM-238 conjugated with  Alexa Fluor® 647.
Further reading:
Leksa V, Godár S, Cebecauer M, Hilgert I, Breuss J, Weidle UH, Horejsí V, Binder BR, Stockinger H: The N terminus of mannose 6-phosphate/insulin-like growth factor 2 receptor in regulation of fibrinolysis and cell migration. J Biol Chem. 2002 Oct 25;277(43):40575-82.
Schiller HB, Szekeres A, Binder BR, Stockinger H, Leksa V: Mannose 6-phosphate/insulin-like growth factor 2 receptor limits cell invasion by controlling alphaVbeta3 integrin expression and proteolytic processing of urokinase-type plasminogen activator receptor. Mol Biol Cell. 2009 Feb;20(3):745-56.
Leksa V, Loewe R, Binder B, Schiller HB, Eckerstorfer P, Forster F, Soler-Cardona A, Ondrovicová G, Kutejová E, Steinhuber E, Breuss J, Drach J, Petzelbauer P, Binder BR, Stockinger H: Soluble M6P/IGF2R released by TACE controls angiogenesis via blocking plasminogen activation. Circ Res. 2011 Mar 18;108(6):676-85.
Leksa V, Ilkova A, Vicikova K, Stockinger H: Unravelling novel functions of the endosomal transporter mannose 6-phosphate/insulin-like growth factor receptor (CD222) in health and disease: An emerging regulator of the immune system. Immunol Lett. 2017 Oct;190:194-200.
Vicikova K, Petrovcikova E, Manka P, Drach J, Stockinger H, Leksa V: Serum and urinary levels of CD222 in cancer: Origin and diagnostic value. Neoplasma. 2018 Sep 19;65(5):762-768.
Ohradanova-Repic A, Machacek C, Donner C, Mühlgrabner V, Petrovcikova E, Zahradnikova A, Viciková K, Horejsí V, Stockinger H, Leksa V: The mannose 6-phosphate/insulin-like growth factor 2 receptor mediates plasminogen-induced efferocytosis. J Leukoc Biol. 2019 Mar;105(3):519-530.
Beletskiy A, Chesnokova E, Bal N: Insulin-like growth factor 2 as a possible neuroprotective agent and memory enhancer-its comparative expression, processing and signaling in mammalian CNS. Int J Mol Sci. 2021 Feb 12;22(4):1849.

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