CD220 INSR (insulin receptor)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Skeletal muscle
Leukocyte
Fibroblast
Endothelial Cell
Epithelial Cell
Lymphoblast
Spleen
Liver
Kidney
Skin
Nerve
Adipocyte
Placenta
Lymphokine
Hepatocyte
95 / 95
400 / 400

Expression
CD220 is expressed widely but at varying levels in mammalian, high in hepatocytes, skeletal muscle, adipocytes and at high levels in placenta and at low levels among subpopulations of PBL and cell lines.  CD220 expression increases during activation of B and T lymphocytes.  Expression is also on leukocytes, fibroblasts, endothelial and epithelial cells.  Expression is in the peripheral nerve, kidney, liver, skin, spleen and lymphoblasts.

Structure
MOLECULAR FAMILY NAME: Belongs to the tyrosine protein kinase family.

CD220 is a single-pass type-1 glycoprotein.  After removal of the 27 aa signal sequence, CD220 is post-translationally cleaved into the α and β chains that are then coavlently linked.
The 731 aa α chain is an entirely extracellular domain which contains 2 fibronectin type-3 domains and 14 potential and N-linked glycosylation sites and the β chain is a tyrosine kinase which contains an 194 aa extracellular region which contains 4 O-linked glycosylation sites, a 26 aa transmembrane domain and a 408 C-terminal cytoplasmic domain containing a tyrosine kinase domain.  CD220 is a cellular receptor for insulin sequence.  

MOLECULAR MASS
Cell Type Unreduced Reduced
400 kDa, 135 kDa α chain 95 kDa β chain

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  CD220 has multiple potential glycosylation sites in both a and b subunits which are linked by disulfide bonds.  The a site is at 13-15 and the b site is at 4.  The α chains contribute to the formation of the ligand-binding domain, while the β chains carry the kinase domain.  Autophosphorylation activates kinase activity and on tyrosine residues is in response to insulin.  The phosphorylation of Tyr-999 is required for IRS1- and SHC1-binding.

POST-TRANSLATIONAL MODIFICATION

After removal of the precursor signal peptide, the insulin receptor precursor, CD220, is post-translationally cleaved into 2 chains, a and b, that are covalently linked.  CD220 is heavily glycosylated.  The 130 kDa a subunits contain 731 aa on an exon 11+ isoform which is wholly extracellular.  The 95 kDa b subunits contain 620 aa.  It is a single membrane spanning domain.  Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake.

Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD220

CD220 binds insulin and IGF-2.  The short isoform has a higher affinity for insulin than the long isoform.

Function
CD220 is the cellular receptor for insulin.  Binding of insulin leads to autophosphorylation of the kinase domain and subsequent phosphorylation of the insulin receptor substrates and the induction of complex signaling cascades within the cell.  It plays a critical role in stimulating glucose uptake.  The insulin/CD220 has a tyrosine-protein kinase activity and functions in the clearance of ligands rather than intracellular signaling.  Signaling by CD220 depends absolutely on activation of the tyrosine kinase following ligand binding.  CD220 is internalized into endosomes where the acidic environoment causes insulin to dissociate and be degraded, thereby preventing insulin-driven re-phosphorylation and enables endosomally associated tyrosine phosphatases to dephosphorylate CD220.  The receptor is then recyled to the cell surface.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD220 IN INTACT ANIMAL

Mutation in CD220 leads to insulin-resistant diabetes mellitus, which can vary in severity.  Insulin-resistance type A is associated with acanthosis nigricans, hirsutism, hyperandrogenism.  Rabson-Mendenhall syndrome is a severe insulin resistance characterized by severe insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities.  Defects in CD220 are also responsinle for the most severe form of insulin syndrome known as Donohue syndrome or  Leprechaunism, which is characterized by interuterine and postnatal growth retardation and death in early infancy.  Both Rabson-Mendenhall and Donohue syndromes are autosomal recessive inherited disorders.




Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD220: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD220: No information.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3643P06213
Antibodies

Revised June 25, 2008


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