CD222 IGF2R (insulin-like growth factor 2 receptor), M6P-R (mannose-6-phosphate receptor)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Heart
Lymphocyte
Granulocyte
Fibroblast
Myocyte
250 / 250
300 / 300

Expression
CD222 is expressed on many cell types such as fibroblasts, granulocytes, lymphocytes and myocytes.  A truncated form of the receptor of 220 kDa is present in human and bovine serum.  Receptor expression is highest at 16-20 days of embryonal development, mainly in the heart, and declines during the postnatal period in rat and mouse tissues.  The majority of CD222 is in the late endosomal/prelysosomal compartment, only about 5%-10% is in the plasma membrane.


Structure
MOLECULAR FAMILY NAME: Belongs to the insulin-like growth receptor family.

CD222 is a single-pass type-1 250 kDa  glycoprotein.  It contains a 40 aa signal sequence, an 134 aa - 167 aa extracellular domain which consists of 15 homologous domains with the 13th domain having a 43 aa insert that is a fibronectin-like collagen-binding domain and 19 N-linked glycosylation sites but not all are used, a 23 aa long transmembrane domain and an 164 aa long carboxyl-terminal cytoplasmic domain whic contains an internalization signal.  CD222 was originally identified as a receptor for insulin-like growth factor 2 (IGF2) and  mannose-6 phosphate (M6P)-containing proteins such as lysosomal hydrolases.  Lysosomal enzymes are sorted to lysosomes by CD222 either from the Golgi, where the enzymes acquire M6P, or from the extracellular space.  The majority of the molecules are approximately 90%-95% and are located intracellularly, only 5%-10% is present on the cell membrane.  The internalization rate seems to be enhanced by ligand induced dimerization of CD222 as well as by phosphorylation of its cytoplasmic serine. 

MOLECULAR MASS
Cell Type Unreduced Reduced
Monocytes 250 kDa, 300 kDa
Fibroblasts 250 kDa 300 kDa

POST-TRANSCRIPTIONAL MODIFICATION: No information.

POST-TRANSLATIONAL MODIFICATION

CD222 has 19 potential N-glycosylation sites some of which utilize palmitoylation and cytoplasmic serine phosphorylation.  Cleavage of the extracellular portion releases a 220 kDa soluble form into the serum and an incomplete glycosylated form of 230 kDa occurs in monocytes.  The position of the cleavage site is unknown.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD222
Molecule Comment
cathepsin B Intracellular/extracellular ligand
cathepsin D Intracellular/extracellular ligand
cathepsin L Intracellular/extracellular ligand
b-glucuronidase Intracellular/extracellular ligand
b-mannosidase Intracellular/extracellular ligand
a-fucosidase Intracellular/extracellular ligand
b-hexosaminidase Intracellular/extracellular ligand
arylsulfase Intracellular/extracellular ligand
b-galactosidase Intracellular/extracellular ligand
phosphomannan Extracellular ligand
latent TGFb Extracellular ligand
LIF (leukemia inhibitory factor) Extracellular ligand
proliferin Extracellular ligand
prorenin Extracellular ligand
herpes simplex virus Extracellular ligand
PI-PLC cleaved GPI anchor in vitro ligand
retinoic Extracellular ligand
IGFII Extracellular ligand
plasminogen Extracellular ligand
thyroglobulin Extracellular ligand
TGFbR-V (400 kDa) Membrane partner
CD87 Membrane partner
GTP-binding proteins Gi-2 Gi-1 = Gi-3 G0 Intracellular ligands, controversial
HA I adaptin Intracellular ligands
HA II adaptin Intracellular ligands



Function
CD222 binds and internalizes a variety of extracellular ligands and directs them to lysosomes and sorts newly synthesized M6P-containing lysosomal enzymes and transports newly synthesized acid hydrolases to lysosomes.  CD222 binds and internalizes IGF2 independently of M6P.   CD222 is a receptor which  participates in the activation of latent TGFb as a receptor for M6P containing latency association peptide (LAP) and CD222 complexes with CD87 and plasminogen for activation of LTGFb.  The main functions of CD222 include internalization of IGF2, internalization of sorting of lysosomal enzymes and other M6P-containing proteins such as latent TGFb as well as regulation of TGFb activity.  
There is controversial evidence for CD222 mediated signal transduction via heteromeric G proteins.  CD222 is used as an anchor by acid lysosomal hydrolases during degradation of pericellular and extracellular proteoglycans.

BIOCHEMICAL ACTIVITY

The biochemical activity of CD222 is the internalization of IGF2 and lysosomal enzymes and the binding and activation of latent TGF
b.

DISEASE RELEVANCE AND FUNCTION OF CD222 IN INTACT ANIMAL

 CD222 has been reported to be involved in cell adhesion and growth regulation of myeloma cells.  CD222 is associated with hepatocellular carcinoma.  CD222 -/- null mice exhibit organ and skeletal abnormalities and die at birth.  The main cause of their death is probably the loss of the CD222 internalization machinery, because CD222 -/- mice in IGF2 -/- or IGF2R -/- background survive.  CD222 is often mutated in several forms of cancer and its is suggested to be a tumor suppressor oncogene.  Proliferin-induced angiogenesis is mediated by CD222.  Chlamydia pneumoniae uses CD222 as a receptor and as a means of infecting endothelial cells.  Activation of CD222 by IGF-II stimulates increased insulin secretion by pancreatic β cells.  Signaling by CD222 promotes exocytosis in insulin-secreting cells. 


Comments
CD222 is involved in lysosomal sorting and internalization.

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD222: No information.

SUBSTRATES

The enzymatic activity is not known.

ENZYMES WHICH MODIFY CD222
Enzyme Comment
TGFb receptor type-V kinase in vivo
casein kinase II in vitro



Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3482P11717
Antibodies
MEM-238   View Reactivity

Revised June 25, 2008


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