CD333 FGFR3 (fibroblast growth factor receptor 3), (achondroplasia thanatophoric dwarfism), JTK4
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Fibroblast
Epithelial Cell
Kidney
Brain Cell
Bladder
Testis
Carcinoma Cell
115 / 115
135 / 135

Expression
CD333 is expressed on fibroblasts and epithelial cells.  Expression is in the brain, kidney, adult testis, but expression is low or nonexistent in spleen, heart and muscle.  In 20-22 week old fetuses expression is high in kidney, lung, small intestine and brain but in a lower level in spleen, liver and muscle.  CD333 is expressed in aggressive bladder carcinomas.

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

CD333 is a single-pass type-1 784 aa glycoprotein.  It contains a 353 aa extracellular domain which contains of 3 Ig-like C2-type domains and 6 potential N-linked glycosylation sites, a 21 transmembrane domain and a 410 aa intracellular cytoplasmic domain which contains 2 ATP binding sites and a 290 aa tyrosine kinase domain that is split by a short insert.  The 3 Ig-like CD2-type domains (D1-D3), a stretch of residues in the linker connecting D1 and D2 known as the "acid box", a heparin binding site in D2.  D2 and D3 form the primary binding pocket for fibroblast growth factor (FGF), whereas D1 and the acid box have an autoinhibitory role.  Binding FGF induces dimerization of CD333 and results in a tetrameric complex.  Essential cofactors associated with this complex are cell-surface heparin sulphate proteoglycans.  CD333 interacting with FGF sets in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation.  It is a transmembrane tyrosine kinase that serves as a high affinity receptor for FGFs.  FGFs are mitogens that can activate a number of intracellular signalling pathways and exert numerous effects depending on the target cell.  The protein encoded by this gene, CD333, is a member of the FGFR family, where the amino acid sequence is highly conserved between members and throughout evolution.   CD333 family members differ from one another in their ligand affinities and tissue distribution. 

MOLECULAR MASS


POST-TRANSLATIONAL MODIFICATION 

Alternative splicing yields 3 different isoforms by RNA splicing.  Epithelial cells show exclusively isoform 2 transcripts while fibroblastic cells show a mixture of isoform 1 and isoform 2.  The most significance is the cell-type specific obligatory splicing that generates two forms of D3 with different FGF binding characteristics.

POST-TRANSCRIPTIONAL MODIFICATION

CD333 has 6 potential N-linked glycosylation sites.  Dimerization promotes autophosphorylation in trans of critical tyrosines in the activation loop that stablizes the receptor in an active conformation and leads to in cis phosphorylation of tyrosine residues within the TK domain.  Intracellular phosphotyrosines serve as binding sites for signal transduction molecules such as SHC, FRS2 and phospholipase Cγ (PLCγ). 

Ligands
LIGANDS AND MOLECULE ASSOCIATED WITH CD333

CD333 associates with acidic and basic FGF with high affinity.

Function
CD333 serves as a high affinity receptor for fibroblast growth factors (FGFs).  FGFs are mitogens that can activate a number of intracellular signalling pathways and exert numerous effects depending on the target cell. 

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD333 IN INTACT ANIMAL

The interaction between FGFs and the FGFRs is very important in the development of the emybro and in wound healing.  FGF signalling is also implicated in tumor growth and angiogenesis.  CD333 is involved in limb induction  and craniofacial development.  This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance.  Knockout mice are viable but have an inner ear defect and bone overgrowth due to chondrocyte hypertrophy.  FGF-induced CD333-mediated signaling plays a critical role in the growth and development in the growth and development of the skeleton.  Mutations in humans are associated with several skeletal disorders including Beare-Stevenson gyrata, Muenke syndrome, Saethre-Chotzen-like syndrome, achondroplasia (short-limb dwarfism), severe achondroplasia wuth developmental delay and acanthosis nigricans, thanatophoric dysplasias types I and II and hypochondroplasia.  Mutations in this gene also leads to Crouzon syndrome (craniosynostosis),  multiple types of lethal skeletal dysplasia, and bladder and cervical cancer.  Many of these mutations are specific nucleotide substitutions and have been found to be germline mutations of paternal.  Abnormal expression of CD333 is linked to a variety of cancers and carcinomas.  Activating mutations appear to play a central role in the development of papillary bladder tumors.  CD333 acts as an inhibitor of induced cell proliferation of normal uroepithelium.  In aggresive bladder carcinomas the level of expression is significantly reduced.  Actove kinases result from the translocation and fusion of CD333 with other proteins are associated with multiple myeloma and peripheral T cell lymphoma.  Other mutations are found in thyroid carcinomas, cervical carcinoma and colorectal carcinoma.  Germline mutations associated with achondroplasia and thanatophoric dysplasis are also associated with 35% of cases of bladder cancer and 25% of cervical cancers.  Also, a chromosomal aberration involving CD333 may be a cause of multiple myeloma. 

Comments
MOLECULAR INTERACTIONS-
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD333: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD333: No information.

ADDITIONAL INSIGHTS

For further information see Walsh, S. et al (2000) Bone 27: 185-195.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 2261P22607
Antibodies

Revised June 25, 2008


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