CD167a DDR1 (discoidin domain receptor family, member 1)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Epithelial Cell
Gastrointestine
Leukocyte
Dendritic Cell
Kidney
Lung
Colon
Brain
Thyroid
Tumor Cell
125 / 125

Expression
CD167a is expressed mainly on normal and transformed epithelial and dendritic cells and is activated by various types of collagen but is weak on immature dendritic cells and B cells.  In the human, CD167a is highly expressed in epithelia especially those found in the mammary gland, kidney, lung, colon, gastrintestinal tract, thyroid, brain epithelial tumors and islets of Langerhans.  In human tumors, CD167a is over-expressed in the breast, ovarian, esophageal, and pediatric brain.  Expression is at low levels in most adult tissues.  In the mouse, it is an early marker for neutroectodermal cells.  CD167a is also expressed in the plasma membrane and is inducible in leukocytes. 



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

CD167a is a single-pass type-1 glycoprotein.  It contains 155 aa discoidin extracellular domain followed by a 200 aa stalk and contains a F/5/8 C-type domain, a transmembrane domain and a intracellular cytoplasmic domain containing a juxtamembrane region and a catalytic tyrosine kinase region.  The extracellular domain is sufficient for collagen binding but the presence of the stalk region enhances this interaction.  CD167a is a receptor tyrosine kinase widely expressed on normal and transformed epithelial cells.  The human gene is composed of 17 exons. There are 8 exons on the extracellular domain, 3 which encode the discoidin domain, 1 exon encodes the transmembrane region, 3 exons on the cytoplasmic region encode the juxtamembrane domain and 5 exons encode the catalytic domain.  Compared to other receptor tyrosine kinases (RTK), the juxtamembrane region of CD167a is significantly longer with 176 aa.  CD167a is partially processed into a 63 kDa membrane-anchored b-subunit and a 54 kDa soluble, extracellular domain-containing an a-subunit, by an unidentified protease.  CD167a belongs to a subfamily of tyrosine kinase receptors with a homology region to the Dictyostelium discoideum protein discoidin I in their extracellular domain.  There are 2 members that have been identified as CD167a (DDR1) and CD167b ( DDR2).  During the cell aggregation of Dictyostelium, the related molecule is secreted and functions as a lectin.  It is thought to be important in the maintenance of morphology, cytoskeletal organization, and the ability to align with other cells during aggregation.  The discoidin domain in the extracellular regions, CD167a and CD167b, are thought to play a role in cell-cell contact and in cell adhesion signaling pathways.

Discoidin domains, also called Factor VIII-homology or DS domains, are found in a variety of other proteins.  Transmembrane proteins with the discoidin domain are CD167b, neurexin, and neuropilin, A5 antigen in Xenopus.  Secreted proteins with the discoidin domain are blood clotting factor 5, blood clotting factor 8, AEBP1, MFG-E8, BA46, Del-1, and XLRS-1.  The kinase domain has high homology to mammalian TrkA, B and C, and to the marine sponge tyrosine kinase receptor GCTK from Geodia cydonium.

MOLECULAR MASS
Cell Type Unreduced Reduced
120 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 3 different isoforms.  CD167a generated 3 isoforms by alternative splicing and are identified as DDR1a, DDR1b and DDR1c.  The longest transcript codes for the c-isoform and translates to a protein with 919 aa.  Compared to the c-isoform, the b-isoform lacks 6 aa inserted between exon 13 and 14.  The a-isoform lacks an additional 37 aa in the juxtamembrane region as a result of alternative splicing of exon 10 to exon 12.  CD167a shows alternative slicing in the juxtamembrane region and the kinase domain.  In humans the longest transcript is DDR1c.  Deletion of 18 bp in the kinase results in the DDR1b isoform.  A cryptic splice acceptor site has been identified 5' of exon 14.  Deletion of exon 11 with 111 bp in the juxtamembrane region of DDR1b results in DDR1a.  A possible mechanism for the production of this splice variant may be the presence of an inverted repeat at the 3' end of the exon/intron boundary which allows the formation of a hairpin structure.  Message stability has not been studied.

POST-TRANSLATIONAL MODIFICATION

The different forms of CD167, DDR1a and DDR1b, are differentially glycosylated.  Several tyrosines become phosphorylated upon receptor activation.  Tyrosine 513 of DDR1b, which is part of the motif LLXNPXY, has been mapped as a phosphorylation site.  About 10% of CD167a is proteolytically processed yielding a 52 kDa soluble protein a-subunit and a 62 kD transmembrane protein b-subunit.  The b-subunit remains in the membrane and the a -subunit can be purified from the supernatant.  The furin recognition site RFRR with 304 aa-307 aa may be utilized for cleavage  or shedding of CD167a.


Ligands
CD167a binds all types of collagen, type-1-6 and 8.

LIGANDS MOLECULES ASSOCIATED WITH CD167a
Molecule Comment
ShcA ShcA binds to LLXNPXpY site of DDR1b
FRS2 FRS2 binds to DDR1a



Function
CD167a functions as an adhesion molecule and is a collagen receptor.  Various types of collagen have been identified as the cognate ligands for both DDR's.  CD167a autophosphorylation is achieved by all collagens tested, type 1-type 6.  CD167a is activated by fibrillar collagens, type 1, 2, 3 and 5, as well as the basement membrane collagen, 4 and 8.  Upon stimulation with collagen, the tyrosine kinase is activated.  Activation follows slow kinetics and maximal activation is seen 2-18 hours after stimulation.  In the alternatively spliced insert of DDR1b, the tyrosine in the sequence LLXNPXY becomes phosphorylated and binds to the PTB domain of the ShcA adaptor protein.  The juxtamembrane region of DDR1a binds to the adaptor FRS2.  CD167a binds and is activated by triple helical collagens and plays a role in cell morphogenesis, differentiation and collagen synthesis.  Activation of CD167a induces expression of the metalloproteases MMP1 (collagenase 1) and MMP2 (gelatinase 1) which degrade collagen and regulate ECM remodeling.  The presence of the discoidin domain in CD167a is thought to be essential for collagen binding.  CD167a activation takes place in the absence of a functional b1 integrin receptor for collagen.  No further downstream target has been identified.  Receptor tyrosine kinases (RTKs) play a key role in communication of cells with their microenvironment.  These molecules are involved in the regulation of cell growth, differentiation and metabolism.  CD167a may be involved in cell-cell interactions and recognition. 

BIOCHEMICAL ACTIVITY

The molecular pathway of CD167a is collagen-induced signaling and is non-proliferative.  CD167a is a tyrosine kinase activated by collagen.  Compared to other tyrosine kinases, CD167a activation follows slow kinetics.

DISEASE RELEVANCE AND FUNCTION OF CD167a IN INTACT ANIMAL

To date, no human genetic disease is known that is linked to CD167a.  CD167a knockout mice are smaller in size than the wild type and females are frequently infertile as blastocytes are often unable to implant in the endometrium.  Females that reproduce fail feed their offspring because the lack of lactation is due to malformation of the mammary gland.  CD167a is overexpressed in several cancers, suggesting a function in tumor progression.
 


Comments
MOLECULAR INTERACTIONS -
PROTEIN AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD167a: No information.

SUBSTRATES

The protease involved in CD167a shedding has not been identified.

ENZYMES WHICH MODIFY CD167a

None have been identified. 

ADDITIONAL INSIGHTS

The binding to collagen and the overexpression in various carcinomas suggest a role of CD167 in tumor invasion and metastasis.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 780Q08345
MouseQ03146AC004211
RatQ63474U48705
Antibodies

Revised June 25, 2008


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