CD171 L1CAM (L1 cell adhesion molecule), N-CAML1(neural adhesion molecule L1)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Neuron
Schwann Cell
Lymphoid Cell
Granulocyte
Bone Marrow
T Cell
B Cell
Monocyte
Lymphocyte
Spleen
Thymus
Dendritic Cell
Glial Cells
Peripheral blood
200 / 200
230 / 230

Expression
CD171 is expressed on cell bodies of post-mitotic neurons of CNS and PNS and on axons of post-migratory neurons.  It is also expressed on pre- or non-myelinating Schwann cells of the PNS and glial cells.  It is present on lymphoid and granulocyte precursor cells in the bone marrow, mature T cells in the thymus and both B and T cells in the spleen.  There is also expression on peripheral blood monocytes, B lymphocytes, and CD4+ T lymphocytes, but not CD8+ T lymphocytes.  Although about 10%-20% of the peripheral blood lymphocytes express both CD171 and CD31, the majority express only 1 or the other.  An intermediate to low expression is evident on human lymphoid and myelomonocytic cells including CD4+ T-cells, a subset of B-cells, monocytes, monocyte-derived DC, follicular DC and renal, urogenital and intestinal epithelial leukemias.  There is intermediate expression on the murine lymph node reticular fibroblasts and strong to intermediate expression described on human tumor cells including neuroectodermal tumor cell lines such as melanoma and neuroblastoma, carcinomas like lung, renal, and skin, and monocytic leukemias.  There is an intermediate to low expression described on the rodent epithelia associated with the kidney, skin, lung, small intestine, colon, urogenital tract, and tongue.


Structure
MOLECULAR FAMILY NAME: Belongs to the immunoglobulin gene superfamily.

CD171 is a single-pass type-1 glycoprotein.  It contains an extracellular domain which contains 6 Ig-like C2-type domains, 5 fibronectin type-3 domains and 21 potential N-linked glycosylation sites, a transmembrane domain and a highly conserved 114 aa or 110 aa cytoplasmic domain of the molecule by the transmembrane domain and by 2 immune tyrosine inhibitory motifs (ITIMs) that contains 6 potential phosphorylation sites and are associated with phosphatases such as SHP-2.  There are 2 peptide sequences, YEGHH and RSLE, which are coded by exons 2 and 27 of the CD171 gene and appear to be specifically spliced out in hematopoietic cells.  CD171 is a transmembrane recognition molecule that belongs to the immunoglobulin supergene family and to the L1/neurofascin/NgCAM family.  An attractive model for the overall structure of CD171 is based on the crystal structure of a related molecule called axonin-1/TAG-1.  According to this model the first 4 immunoglobulin domains of CD171 family members bind to one another in an antiparallel alignment.  

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Neurons 200 and 180-190 kDa Smaller MW band is faint
Neurons 140, 80 and 40 kDa Cell-associated degradation products
Neuroblastoma 200-215 kDa Single band reported
Melanoma 215-220 and 190-200 kDa Smaller MW band is faint
Monocytes 210-220 kDa Single band reported
T-cells 200-220 kDa Size of band varies with T-cell activation
Epithelial cells 220-230 and 190-210 kDa Two separate bands reported

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  The CD171 gene is comprised of 29 exons of which 28 are coding exons.  Exons 2 and 27 are neural-specific.

POST-TRANSLATIONAL MODIFICATION

CD171 is glycosylated, containing 21 potential N-linked glycosylation sites within its ectodomain.  There are 6 potential phosphorylation sites present in the CD171-cytoplasmic domain.  The conserved dibasic sequences in the 3rd fibronectin-like domain of CD171 are susceptible to serine protease cleavage.  The CD171 ectodomain can be shed as a result of post-translational cleavage by disintegrin metalloproteinase (ADAM).  Plasmin cleaves within the sequence RK-HSK-RH 846 to CD170 at he same site.

Ligands
CD171 bind itself, neurocan, phosphocan, laminin and the integrins CD51/CD61  
(αVβ3) and CD41/CD61 (αIIβ3) and CD49e/CD29 (α5β1) and mediates homotypic adhesion.  Binding to the integrin CD49b/CD29 (α2β1) has been demonstrated in the mouse but not in humans.  The possible explanation is that while there are 2 RGD motifs, RGDG and RGDS, in the 6th IgSF domain of mouse CD171, only RGDG is found in the human.  CD171 binds CD9, CD24, CD56, CD142 and CD166 integrins.

LIGANDS AND MOLECULES ASSOCIATED WITH CD171
Molecule Comment
CD171 trans (molecules on the apposing cell) interacting elements include CD171 (homophilic), neurocan, phosphocan, and laminin
Neurocan trans (molecules on the apposing cell) interacting elements include CD171 (homophilic), neurocan, phosphocan, and laminin
Phosphocan trans (molecules on the apposing cell) interacting elements include CD171 (homophilic), neurocan, phosphocan, and laminin
Laminin trans (molecules on the apposing cell) interacting elements include CD171 (homophilic), neurocan, phosphocan, and laminin
CD9 cis (molecules on the same cell) interacting elements described include CD9, CD24 (heat stable antigen), CD56 (NCAM), Axonin-1/TAG-1
CD24 (heat stable antigen) cis (molecules on the same cell) interacting elements described include CD9, CD24 (heat stable antigen), CD56 (NCAM), Axonin-1/TAG-1
CD56 (NCAM) cis (molecules on the same cell) interacting elements described include CD9, CD24 (heat stable antigen), CD56 (NCAM), Axonin-1/TAG-1
Axonin-1/TAG-1 cis (molecules on the same cell) interacting elements described include CD9, CD24 (heat stable antigen), CD56 (NCAM), Axonin-1/TAG-1
CD51/CD61 (a-v b-3) integrin reported to recognize CD171 include CD51/CD61 (αVb3), CD41/CD61 (aII b3), CD49e/CD29 (VLA-5 or a5b1), and CD49b/CD29 (a2b1)
CD41/CD61 (a-IIb b-3) integrin reported to recognize CD171 include CD51/CD61 (αVb3), CD41/CD61 (aIIbb3), CD49e/CD29 (VLA-5 or a5 b1), andCD49b/CD29 (a2b1)
CD49e/CD29 (VLA-5 or a-5 b-1) integrin reported to recognize CD171 include CD51/CD61 (αVb3), CD41/CD61 (aIIbb3), CD49e/CD29 (VLA-5 or a5b1), and CD49b/CD29 (a2b1)
a-9/CD29 (b-1) integrin reported to recognize CD171 include CD51/CD61 (αVb3), CD41/CD61aIIbb3), CD49e/CD29 (VLA-5 or a5b1), and CD49b/CD61 (a2b1)
ankyrins CD171 cytoplasmic domain interacts with ankyrin and kinases
kinases CD171 cytoplasmic domain interacts with ankyrin and kinases


Function
CD171 functions as a multidomain cell adhesion molecule that mediates homotypic and heterotypic cell-cell interaction and binds laminin, integrins and proteoglycans containing chondroitin sulphate.  CD171 mediates dynamic neurological processes which have been attributed to homphilic L1-L1 ligation.  These include neural cell migration, neurite extension, Schwann cell-axon interaction, synaptogenesis, myelination, neuronal cell survival, and the induction of long-term potentiation.  Memory consolidation may be linked to changes in neuronal expression and glycosylation of CD171 and CD54.  CD171 has been shown to support interactions with a variety of heterophilic ligands including proteoglycans, integrins, CD9, CD24, CD56, TAG-1/Axonin-1, CD142 and CD166.  Since CD31 and CD171 are expressed on different subsets of lymphocytes, it is proposed that CD51/CD61/CD171 interaction may serve as an alternative to CD51/CD61/CD31 interaction for lymphocyte arrest and initiation of migration on endothelial cells. 

BIOCHEMICAL ACTIVITY

Signaling mediated by CD171 binding can occur through cis interactions with other molecules or through CD171 itself.  The signaling involves phosphorylation as well as binding of the cytoskeletal element ankyrin.  Interaction with the membrane skeleton is regulated by CD171 adhesive activity and can involve pertussis-sensitive G-proteins, protein kinase C, the release of arachidonic acid and influx of intracellular calcium through L-type and Nptype channels.  Internalization of CD171 promotes activation of members of the MAP kinase cascade in a src-dependent manner.  This pathway involves phosphotidylinositol-3-kinase and Rac-1. 

DISEASE RELEVANCE AND FUNCTION OF CD171 IN INTACT ANIMAL

CD171 supports the haptotatic migration and the invasion of tumor cells and can function as a co-stimulatory molecule in T-cell activation in vitro.  CD171 plays a role in kidney morphogenesis, lymph node architecture, T cell costimulation and in neurohistogenesis and homotypic interaction and plays an important role in nervous system development, including neuronal migration and differentiation.  Mutations in the CD171 gene are responsible for an X-linked recessive neurological disorder in man, the CRASH syndrome, associated with hydrocephalus due to stenosis of the aqueduct of Sylvius 1 (HSAS1, HSAS), mental retardation, aphasia, MASA, spastic paraplegia type 1 (SPG1), Hirschaprung disease (HSCR) and ACC.  CD171-deficient mice have neuropathologies consistent with the CRASH syndrome in man.  The findings include dilated brain ventricles, a reduction in the size of the corticospinal tract with errors in corticospinal axon guidance, abnormal morphogenesis of cortical dendrites and developmental defects in the hippocampus and corpus callosum as well as defective interaction between axons and Schwann cells, and a poor performance in spatial learning has been reported.  In Drosophila, mutations in the CD171-type gene neuroglian result in axonal pathfinding defects and embryonic lethality.  Fibroblasts genetically modified to express CD171 have been shown to promote nerve generation in rats.  Ethanol-mediated disruption of CD171-dependent processes has been suggested to be involved in the pathogenesis of alcohol-related neurodevelopmental disorders including fetal alcohol syndrome.  Remodeling of lymph node reticular matrix during an immune response is blocked in mice by an anti-CD171 antibody.


Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD171

See Enzymes below.

SUBSTRATES

No intrinsic catalytic domains are present in CD171.

ENZYMES WHICH MODIFY CD171
Enzyme Comment
p90rsk Phosphorylates serine 1152 of the CD171 cytoplasmic domain
Casein kinase II Phosphorylates serine 1181 of the CD171 cytoplasmic domain
ERK-2 Phosphorylates serine 1204 and serine 1248 of the CD171 cytoplasmic domain
CEK5 Tyrosine phosphorylation of CD171 by the Eph kinase CEK5 has been demonstrated

ADDITIONAL INSIGHTS

In vertebrate species several CD171-related genes are present, which include neurofascin, Nr-CAM and CH-L1.  The contribution of homophilic L1-L1 interaction to neural developmental processes is now well established.  The functional significance of heterophilic CD171 interactions, and the role of nonneural CD171, is only now starting to be addressed.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3897P32004
MouseS05479P11627X12875
Antibodies

Revised June 25, 2008


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