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CADHERINS

STICKING TOGETHER

    The first challenge which faced multicellular organisms was how to be multicellular.  In multicellular organisms, cells must adhere and interact with each other, and with the matrix around them (as in the images of the hydra body wall, the endostyle of a primitive chordate, or human skin below). 

HYDRA CHORDATE
SKIN

This is just as true in human cells as it is in those of simpler animals.  Not surprisingly, human cells interact with their surroundings using members of the same gene families which are utilized by the cells throughout the animal kingdom: cadherins, selectins, fibronectins, and immunoglobulins.

      Cell adhesion in the simplest invertebrates determines whether single cells adhere to form a colony.  In higher invertebrates, cell adhesion is an essential to establish tissues and as part of the immune response as blood cells adhere to parasites to encapsulate them (Johansson, 1999).  A number of domains evolved before the evolution of the most primitive modern animal group (sponges) which allow interaction between cells and their surrounding matrix: fibronectin, scavenger receptor cysteine-rich domains (SRCR), and short consensus repeats (SCR) (Muller, 2001).

     It appears that some of the proteins that animals use for cell adhesion existed prior to the evolution of multicellular animals.  Choanoflagellates are unicellular protists which possess both cadherin and lectin domains.  Yeasts possess a molecule similar to α integrin and cellular slime molds possess Ig-like homologs of CAM molecules (Hartwood, 2004).

 

 

CADHERIN

     The cadherin gene family produce calcium-dependent proteins which function in cell to cell adhesion.  They are important in embryonic development (beginning with the adhesions which hold early embryonic cells together) and help determine tissue structure.  The cadherins mediate cell to cell interactions, and their action is calcium-dependent.  Their extracellular domains can contain multiple cadherin motifs.  Most cadherins are expressed in more than one type of tissue and a single cell can express more than one kind of cadherin.  Five cadherins are clustered on human chromosome 16q21 (cadherins 1,3,5,8, and 11).

      In chordates, the “classic” cadherins share the organization of five tandem cadherin repeats.  Cadherins then form homodimers which attach to dimers of other cells.  The cytoplasmic domain of classic cadherins interacts with proteins called catenins.  Desmogleins, desmocollins, and “nonclassiccadherins have the same extracellular structure but vary in their intracellular domains which determine which cytoplasmic elements they interact with (Hill, 2001).    A number of cadherins also possess EGF and laminin G domains to form what is referred to as the primitive classic cadherin (PCCD) domain which is known from both vertebrates and protostomes (Hill, 2001).  The PCCD was deleted from the classical cadherins in chordates (Oda, 1999).

      Unicellar choanoflagellates possess cadherin domains in their genome (Hartwood, 2004).  The lack of cadherins in sponges may have been one of the factors contributing to the lack of organizational novelty in the history of the group (Nichols, 2006). Cadherins are very important in invertebrates (Johansson, 1999).  Nematodes and flies possess classic cadherins which interact with catenins although their extracellular domains are more variable. The hmr-1 gene in C. elegans has two promoters which produce two forms, one of which is required for the development of epithelia and the other for the development of neural tissue.    Nematodes and flies are known to have 13 and 17 cadherins, respectively, of which 2 nematode and 3 fly cadherins are ‘classical’ cadherins homologus to those of vertebrates.  Flies possess two classic cadherin genes, one required for the development of epithelia and the other for the development of neural tissue (Broadbent, 2002; Hill, 2001).  In insects, the cadherin BT-R1 is essential for the development of the midgut (Midboe, 2003). 

     In vertebrates, cadherin genes are expressed throughout the nervous system and, given their high concentration at synapses, seem to function in the formation and maintenance of synapses (Yanase, 2004).   A neuromuscular synapse is depicted below.

NEUROMUSCULAR
   Different cadherin proteins become expressed only in specific neural nets within the central nervous system during development.  Borders of expression for specific cadherin genes often coincides with organization regions of the developing nervous system (Redies, 2003).  Cadherins are required for the development of the cerebellum in zebrafish (Liu, 2004c).  In mammals, cadherins are involved in the migration of cerebellar Purkinje cells (pictured below), perhaps through homotypic adhesion between cadherin molecules (Luo, 2004).
CEREBELLUM
     The cadherin superfamily can be divided into at least 6 subfamilies: the classical cadherins, the nonclassical cadherins, desmocollins, desmogelins, protocadherins, and Flamingo cadherins.  In addition to these subfamilies, there are other isolated genes which include most of the cadherins known in invertebrates (Nollet, 2000).  It is likely but not certain that cadherins and protocadherins were derived from a common ancestral gene (Nollet, 2000).
INTESTINE

Cadherin 1 composes part of epithelial intermediate junctions (as in the epithelial lining of the frog intestine above).  Without any cadherin (homozygous mutants), the cells of an embryo cannot form a morula and dissociate.  Mutations can cause a number of cancers (epithelial, ovarian, endometrial, and stomach cancers) and susceptibility to the food-borne infection listeria monocytogenes.

 

Cadherin 2 is expressed in neurons and is one of the first proteins to show left/right asymmetry during development..

 

Cadherin 3 is expressed in the placenta.  Mutations cause hypotrichosis with juvenile macular dystrophy.

 

Cadherin 4 is expressed in the brain and other tissues.

 

Cadherin 5 is expressed in vascular endothelia and mutant mice die.

 

Cadherin 6 is expressed in the kidney and brain.

 

Cadherin 7 is expressed in the testes, brain, and prostate.

 

Cadherin 8 is expressed in the brain.

 

Cadherin 10 is expressed in the kidney and brain.

 

Cadherin 11 is expressed in osteoblasts.

 

Cadherin 12 is expressed in the brain.

 

Cadherin 13 has its highest expression in the heart.

 

Cadherin 15 is involved in the differentiation of skeletal muscle.

 

Cahderin 16 is expressed in renal tubules (such as those of the frog pictured below).

GLOMERULUS

Cadherin 17transports peptides in the GI tract and is important for the transport of drugs.

 

Cadherin 18 is expressed in the CNS.

 

Cadherin 19 is widely expressed throughout the body.

 

Cadherin 20 is expressed in the brain and placenta (placenta pictured below).

PLACENTA

Cadherin 23 is expressed in the ear and mutations lead to Usher syndrome.

 

 

Cadherin EGF LAG seven-pass G Type Receptors (CELSR)

CELSR1has a variety of domains including cadherin repeats, EGF-like repeats, and laminin repeats.  It is expressed in the fetal brain and lung and the adult CNS (especially ependymal cells). 

CELSR2 has its highest expression in the brain and testes.

CELSR3 is expressed in the brain.

 

 

PROTOCADHERINS

Protocadherins are more closely related to each other than to the “classical” cadherins.  The domains which are divided by multiple introns in the cadherin genes are single in the protocadherins.  Protocadherins possess 6 extracellular domains in addition to their transmembrane domain and have unusually long exons (2400 nucleotides).  They are highly expressed in the nervous system.  Protocadherin homologs are known in Drosophila and the existence of 3 clusters of protcadherin genes on human chromosome 5q31 suggests that gene duplication has produced some of the diversity of the gene subfamily (Wu, 2000).

     Protocadherins are the largest subfamily of cadherins.  Mammalian genomes analyzed to date possess about 70 protocadherins organized in large clusters (chromosome 5q31, 13q21, and Xq21 in humans). The union of constant and variable regions occurs in α and γ protocadherins on 5q31.  It seems that the clusters of protocadherins are unique to vertebrates (Frank, 2002).

 

 

Protocadherin α1/CNR

      One group of protocadherins, the CNR/Pchhα family also function in synapses and interact with the Reelin and Fyn protein, which function in a variety of processes, including emotion and learning.  The CNR family (cadherin-related neuronal receptor) share a unique cytoplasmic domain which interacts with a nonreceptor tyrosine kinase (Fyn).  In humans, mice and rats, the CNR/Pchhα family exists as a tandem set of genes occupying between 230 and 250 kilobases.  The CNR gene cluster is located on human chromosome 5q31 and has been identified as an area which may be involved in schizophrenia.

 (Yanase, 2004; Sugino, 2000).

     In the immune system, diversity of antibody and T cell receptors is created in the splicing of variable regions onto a constant region which is not rearranged.  In protocadherins, a single variable exon is attached onto the 3 constant exons, similar to the class switching which occurs in immune receptors.  Not only do rodents and humans share clusters of these genes, but the organization of constant and variable exons with in the genes are conserved.  The CNR genes share 3 constant exons which are downstream from a tandem array of about 15 variable exons.  The variable exons are spliced onto the constant ones.   The variable regions of human CNR cluster 1-8 are homologous to regions found in mice and they are organized in the same sequence.  Although humans lack a CNR3 gene which is known in mice, there is a homologous pseudogene in the human genome  (Yanase, 2004; Sugino, 2000; Hamada, 2001).

 

 

     In the following depiction of the Pcdhα families in 3 mammalian genomes, the red regions are constant regions which interact with intracellular tyrosine kinase .  The blue and purple regions are variable which, one of which is attached to the constant regions in forming the protein.

PROTOCADHERIN GENES
PROTOCADHERIN GENES
PROTOCADHERIN GENES

Protocadherin -1

 

Protocadherin 3 is expressed in the brain.

 

Protocadherin 7 is expressed in the brain and the heart.

 

Protocadherin 8 is expressed in the brain and the heart.

 

Protocadherin 9 is widely expressed throughout the body’s tissues.

 

Protocadherin 10 is expressed in the olfactory bulb, many parts of the limbic system, and in specific areas of the cerebellum (Frank, 2002).

 

Protocadherin 11 is only on the X chromosome in most mammals (from marsupials through Old World monkeys).  It is present on both the X and Y chromosomes in orangutans, gorillas, and humans (but not chimps).

 

Protocadherin 12 is expressed in most tissues and is expressed at higher levels in tissues which have a greater blood supply.

 

Protocadherin 16 is expressed in fibroblasts, such as those present in tendons.

There are at least 53 protocadherin genes located in 3 clusters on chromosome 5q31.

 

The a cluster contains genes PCDHA 1 through 13 and PCDHC1 and 2.

 

The b cluster contains genes PCDHB1 through 16.

 

The g cluster contains genes PCDHGA 1 through 12, PCDHGB 1 through 7, and PCDHGC3 through 5.

 

 

There are two classes of cadherin which are expressed in desmosomes: desmogleins and desmocollins.  These glycoproteins hold the cells together and maintain the integrity of the epithelial lining.

 

 

Desmocollin 1 is only present in epithelia which will be keratinized.

Desmocollin  2 is expressed in internal epithelia.

Desmocollin 3 is expressed in basal layers of the epidermis (the basement membrane where the human epidermis contacts the dermis is pictured below).

BASEMENT MEMBRANE

Desmoglein 2 is expressed in the colon.

Desmoglein 3 is expressed on keratinocytes.  In the autoimmune disease pemphigus vulgarus, immune cells attack this protein causing the loss of cell adhesion.

 

FAT-like cadherins exist in vertebrates, nematodes, and flies (Hill, 2001).  The three fat homologues are expressed in distinct regions of the developing mammalian brain (Mitsui, 2002).

 

FAT1 is the homolog of the FAT tumor suppressor in Drosophila.  It has 34 cadherin repeats and is expressed in epithelia, endothelia, and smooth muscle (Nollet, 2000; OMIM).

 

FAT2 is only expressed in the cerebellum and is required for cerebellum development (Nollet, 2000).

 

FAT3 is a large mammalian protein that contains multiple cadherin and EGF-like motifs (Mitsui, 2002). 

 

The Ret proto-oncogene interacts with tyrosine kinases.  Mutations can cause cancer and Hirschsprung disease (Nollet, 2000).  Ret-like cadherins exist in vertebrates, nematodes, and flies (Hill, 2001). 

 

Seven-helix transmembrane cadherins (which include the secretin GPCRs) are known in vertebrates, nematodes, and flies (Hill, 2001).

 

Flamingo cadherins are known in vertebrates and flies (Nollet, 2000).

 

 

INTEGRIN

INTEGRIN

     The integrin gene family in animals functions in cell adhesion, cell signaling, and (in vertebrates) specialized functions in embryonic development, platelet plug formation, and leukocyte migration.  Most are receptors for proteins of the matrix surrounding cells but some interact with other cell membrane proteins.  Integrins are composed of nonhomologous a and b subunits.  Both a and b subunits are known throughout the animal kingdom, including in sponges and there evidence that integrin-like molecules exist in plants and fungi (Brower, 1997).   Yeasts possess a molecule similar to α integrin which functions in adhesion (Hartwood, 2004).  Sponges possess integrins, an extracellular matrix, and transcription factors of the ets, paired-box, and homeobox (several including an NK class gene and one Hox-like gene) classes (Peterson, 2002; Muller, 2001).  Integrins bind a variety of substrates including collagen, laminin, fibronectin, and coagulation factor X.  Peroxidase can bind integrin in an immune respose which seems conserved in coelomates (Johansson, 1999).

 

 

     Integrins are cell-cell or cell-matrix heterodimers composed of one of a set of a subunits (120-180 kD) and b subunits (90-110 kD).  Given the number of a and b genes, over 100 different combinations are possible. 

 

a SUBUNITS

     There are 2 groups of a subunits: one group share a 180 amino acid insertion (the I integrins) which is not found in the other group (the non-I integrins).  The non-I integrins exist in clusters on chromosomes 2, 12, and 17.  They exist near the clusters of HOX genes although the significance of this is not clear.

 

ITGA1 forms the laminin/collagen receptor of neurons and hematopoetic cells with ITGB1.

 

ITGA2 possesses an I domain and may serve as a receptor for collagen.  In platelets it is involved in alloimmunity and thrombocytopenia.

 

ITGA3 associates with the protein reelin in the brain along with ITGB1.

 

ITGA4 functions in cell to cell adhesion and as a receptor for fibronectin.

 

ITGA5 serves as a receptor for fibronectin.

 

ITGA6 mutations can cause epidermolysis bullosa.

 

ITGA7 is a receptor for laminin 1 in the basement membrane.  Mutations in humans cause myopathy and in mice mutations cause muscular dystrophy.

BASEMENT MEMBRANE

ITGA8 is most highly expressed in smooth muscle and is required in the kidneys and in hair cells.

 

ITGA9 is expressed in epithelia, skeletal and smooth muscle, and the liver.

 

ITGA10 complexes with ITGB1 in cartilage.

 

ITGA11 is most highly expressed in the uterus and heart (smooth muscle of the uterus is pictured below).

uterus

ITGV is involved in development and angiogenesis.

 

ITGE has a unique 55 amino acid region near its I domain.

 

ITGL is involved in the compartmentalization of lymphoid tissue.

 

ITGD

 

ITGM is expressed in lymphocytes and is involved in the inflammation which accompanies atherosclerosis.

 

ITGX

 

b SUBUNITS

ITGB1 associates reelin in the embryonic brain, serves as a fibronectin receptor, and mutations in mice cause brain abnormalities and death.

 

ITGB2 mutations cause leukocyte disorders and, in mice, chronic inflammatory skin disorders.

 

ITGB3 is expressed in platelets and endothelial cells.  Mutations can cause Glanzmann thrombasthenia and one polymorphism affects the formation of alloantigens after organ transplants and transfusions. ITGB3 forms part of the von Willebrand factor.

 

ITGB4 forms a receptor for laminins along with ITGA6.  Mutations are involved in epidermolysis bullosa and carcinomas.

 

ITGB5 binds to matrix protein vitronectin.  Mutations in mice increase tumor formation and growth.

 

ITGB6

 

ITGB7 is expressed in leukocytes.

 

ITGB8 functions in synapses with ITGA5.

 

ITGBL1 is most highly expressed in the aorta.
SELECTINS

Selectin P is expressed in endothelia and metamegakaryocytes.  It affects white blood cell movement and is increased in atherosclerotic plaques.

 

Selectin E has both lectin and EGF-like domains.  It is involved in interactions between leukocytes and endothelia and in atherosclerosis.

 

Selectin L has one lectin and 1 EGF domain and is involved in neutrophil adhesion (the purple cell below is a human neutrophil).

neutrophil

OTHER PROTEINS

 

The tetraspanin superfamily of proteins include membrane proteins which function in adhesion and cellular movements (Kollmar, 2001).

 

Tight junctions are a chordate feature, although they have also been found in blood-brain and blood-testis barriers in arthropods.  Mammals possess about 20 claudin genes which maintain junctions such as the tight junctions of the blood-brain and blood-testis barriers.  Many of these genes (and even their intron position) predate the split of bony fish and tetrapods (Kollmar, 2001).