CD331 FGFR1 (fibriblast growth factor receptor 1)(fms-related tyrosine kinase 2, Pfeiffer syndrome), FLT2, FLG
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Fibroblast
Epithelial Cell
Endothelial Cell
Breast
Cancer cell
130 / 130

Expression
CD331 is expressed on fibroblasts, endothelial and epithelial cells.  Wide expression is in adult and fetal tissues and over expressed in breast cancers.

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

CD331 is a single-pass type 1 801 aa glycoprotein.  It contains a 355 aa extracellular domain which contains of 3 Ig-like C2-type domains and 8 N-linked glycosylation sites, a 21 aa transmembrane domain and a 425 aa intracellular cytoplasmic domain which has 2 ATP binding sites and a 290 aa protein kinase domain that is split by a short insert.  The 3 Ig-like C2-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 CD331 and results in a tetrameric complex.  Essential cofactors associated with this complex are cell-surface heparin sulphate proteoglycans.  CD331 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, CD331, is a member of the FGFR family, where the amino acid sequence is highly conserved between members and throughout evolution.  

MOLECULAR MASS

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 18 different isoforms by RNA splicing.  However, not all isoforms have been fully characterized but the most significance is the cell-type specific obligatory splicing that generates two forms of D3 with different FGF binding characteristics.

POST-TRANSLATIONAL MODIFICATION

CD331 has 8 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.  Autophosphorylation of Tyr653 and Tyr654 is essential for the regulation  of kinase activity.  Intracellular phosphotyrosines serve as binding sites for signal transduction molecules such as SHC, FRS2 and phospholipase Cγ (PLCγ).  Autophosphorylated Tyr66 is the binding site for PLCγ.  Binding of CD331 and heparin promotes autophosphorylation on tyrosine residues and activation of the receptor.

Ligands
LIGANDS AND MOLECULE ASSOCIATES WITH CD331

CD331is a high affinity receptor for acidic and basic FGFs.

Function
CD331 serves as a high affinity receptor for fibroblast growth factors (FGFs).  They are mitogens that can activate a number of intracellular signalling pathways and exert numerous effects depending on the target cell.  The receptor proteins play a role in important processes such as cell division, regulation of cell growth and maturation, and formation of blood vessels. 

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD331 IN INTACT ANIMAL

This particular family member binds both acidic and basic fibroblast growth factors.  The interaction between FGFs and FGFRs is very important in the development of the embryo and in wound healing.  During development of the embryo, FGF-induced CD331-mediated signaling plays a critical role in morphogenesis by regulating cell proliferation, differentiation and migration.  In adults, CD331 mediated signaling is involved in tissue repair and wound healing, tumor angiogenesis tumor growth.  CD331 is involved in limb induction, cardiomyocyte and liver development.  CD331 is thought to play an important role in the development of the nervous system.  This protein may also help regulate the growth of long bones, such as large bones in arms and legs.  Mutations in this gene have been associated with Pfeiffer syndrome, which is characterized by craniosynostosis sydrome (premature fusion of cranial structures) and broad thumbs and toes.  CD331 is also associated with the Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, stem cell leukemia lymphoma syndrome and autosomal dominant Kallmann syndrome 2.  Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative syndrome (EMS) disorder.  EMS is characterized by eosinophilia, myeloid hyperplasia and lymphoblastic lymphoma.  The FGF fusion proteins are constitutive tyrosine kinases that have transforming activity.  CD331 is a potential target of tyrosine kinase inhibitors currently under development for use in the treatment of various cancers.  Alterations in CD321 expression or translocation and fusion of FGF with other genes are associated with a variety of malignancies.  Over-expression of CD331 is associated with breast cancer and astrocytomas whereas abnormal expression occurs in prostate cancer and pancreatic adenocarcinoma.

Comments
MOLECULAR INTERACTIONS-
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD331: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD331: No information.

ADDITIONAL INSIGHTS

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


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 2260P11362
Antibodies

Revised June 25, 2008


Contact us: Webmaster |  509-335-9515 | Accessibility | Copyright | Policies
College of Veterinary Medicine Washington State University, Pullman, WA, 99164-7010 USA
Copyright 1995-2003 Washington State University