CD221 IGF1R (insulin-like growth factor 1 receptor), IGFR
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Fibroblast
Nonhematopoietic Cell
Leukocyte
90 / 90
135 / 135

Expression
CD221 is expressed on a variety of tissues, leukocytes and a variety of nonhematopoietic cells.  CD221 is expressed widely but at varying levels in mammalian tissues.  High expression is detected in fibroblasts and skeletal tissues and at low levels or absent in hepatocytes and adipocytes.  It is generally expressed at low levels on cells of the immune system and cell lines.  CD221 expression has been reported to increase, in some studies, on activated resting T cells and in other studies, to decrease following activation.  CD220 is widely expressed among fetal and postnatal tissues and is overexpressed in many tumors.

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

CD221 is a single-pass type-1 1367 aa glycoprotein.  It contains a 30 aa signal sequence,
which is cleaved by furin protease between a 708 aa-711 aa α chain and 712-1337 aa β chain which are disulphide-linked.  The α chain extracellular domain has 11 potential N-linked glycosylation sites.  The α chain is entirely extracellular which contains 2 large homologous domains which are separated by a cysteine-rich region and the β chain contains a 906 aa -929 aa extracellular region which contains 5 N-linked glycosylation sites, a 408 aa transmembrane domain and a 973 aa - 1229 aa intracytoplasmic domain which contains a tyrosine kinase domain that is flanked by a juxtamembrane region and a C-terminal tail that contains phosphotyrosine binding sites for signaling molecules.  CD221 is an orphan insulin and is related to the epidermal frowth factor receptor (EGFR) family.

MOLECULAR MASS
Cell Type Unreduced Reduced
135 kDa α subunit, 90 kDa β subunit

POST-TRANSCRIPTIONAL MODIFICATION

CD221 has multiple potential glycoylation sites in both the a and b subunits.  Tetramer of 2 α and 2 β chains are linked by disulfide bonds.  The  135 kDa α chains contribute to the formation of the ligand-binding domain, while the 90 kDa β chains carries the kinases domain.  The cytoplasmic domain of the β subunit is autophosphorylated on tyrosine residues in response to insulin-like growth factor I (IGS1).  The phosphorylation of Tyr-980 is required for IRS1- and SHC1-binding.

POST-TRANSLATIONAL MODIFICATION

After removal of the precursor signal peptide, the insulin receptor precursor, CD221 is post-translationally cleaved into 2 chains, a and b that are covalently linked.  The a subunit contains 706 aa which are extracellular.  The b subunits contains 626 aa.  It contains a single membrane spanning domain.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD221

CD221 binds insulin-like growth factor 1 (IGF-I) with high affinity as well as IGF-II and insulin.

Function
CD221 is the receptor for insulin-like growth factors IGF-I and IGF-II.  Activation of CD221 results in the initiation of complex signaling cascades and the pathways involved remain unclear.  IGF-I activated CD221 mediates mitogenic signaling and in vitro provides anti-apoptotic signaling in response to a wide range of apoptotic stimuli.  When over-expressed and ligand-activated, CD221 acts as a cellular oncogene and participates in cellular transformation.  Overexpression and its ligands have been observed in a variety of human tumors.  CD221 functions in the clearance of ligands rather than intracellular signaling.  Signaling by CD221 depends on activation of the tyrosine following ligand binding.  CD221 binds insulin-like growth factor with a high affinity and has a tyrosine kinase activity.  The insulin-like growth factor 1 receptor plays a critical role in transformation events.  Cleavage of the precursor generates α and β subunits.  It mediates insulin stimulated DNA synthesis and CD221 stimulated cell proliferation and differentiation.  It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. 

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD221 IN INTACT ANIMAL

Knockout mice are bown weighing less than half the normal weight and die soon after birth.  The development of null mice is first affected between days 11 and 12.5 embryogenesis.  The growth retartation is characterized by widespread organ hypoplasis as a result of an extended transition through all stages of the cell cycle.  Embryonic fibroblasts derived from CD220 knockout mice cannot be transformed by a variety of viral and cellular oncogenes.  Restoration of CD221 expression reverses this effect.  CD221 is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival.  CD221 expression levels are a prognostic indicator in some tumors such as breast and gastric cancers, and the receptor is a therapeutic target for the development of anti-tumor agents.  The CD221 receptor gene is subject to inprinting.  Biallelic expression is associated with Beckwith-Wiedemann syndrome, a congenital growth disorder causing large organs.

 


Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD221: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD221: No information.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3480P08069
Antibodies

Revised June 25, 2008


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