Laminin–111 (also "laminin–1") is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

of the type known as

laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

s. It was among the first of the laminin isoforms to be discovered.Aumailley, M., Bruckner-Tuderman, L., Carter, W. G., Deutzmann, R., Edgar, D., Ekblom, P., & Yurchenco, P. D. (2005). A simplified laminin nomenclature. ''Matrix biology'', 24(5): 326-332. The "111" identifies the isoform's chain composition of α1β1γ1. This protein plays an important role in

embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

. Injections of this substance are used in treatment for

Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis fol ...

, and its cellular action may potentially become a focus of study in

cancer research Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure. Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate and ...

Distribution

The distribution of the different laminin isoforms is tissue-specific.Durbeej, M. (2010). Laminins. ''Cell and Tissue Research'', 339(1): 259-268. Laminin–111 is predominantly expressed in the embryonic

epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...

, but can also be found in some adult

such as the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

testis A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...

ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...

, and brain

blood vessels The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...

.Ekblom, M., Falk, M., Salmivirta, K., Durbeej, M., & Ekblom, P. (1998). Laminin isoforms and epithelial development. ''Annals of the New York Academy of Sciences'', 857(1): 194-211. Different levels of expression of α chains have a large influence on the differential expression of laminin, thereby determining the isoform produced. From studying a mouse model, it was found that

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

s present in the parietal

endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...

regulate the expression of the α1 and large amounts of laminin-111 are produced.

Functions

The synthesized laminin–111 formed in an embryo contributes to the formation of

Reichert’s membrane Reichert's membrane is an extraembryonic membrane that forms during early mammalian embryonic development. It forms as a thickened basement membrane to cover the embryo immediately following implantation to give protection to the embryo from the u ...

, a thick extra-embryonic basement membrane.Minler, J.H. and Yurchenco P.D. (2004). Laminin functions in tissue morphogenesis. ''Annual Review of Cell and Developmental Biology'', 20:255-284. When the laminin α1 chain is deficient in an organism, an embryo dies, likely as a result of a defective Reichert’s membrane due to a lack of laminin–111 being produced. Laminin-111 has been identified as a crucial molecule for development of the embryo as shown by the consequences that occur when laminin-111 is lacking. Laminin-111 is expressed very early on in development and is present in the

blastocyst The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the ''embryoblast'' which subsequently forms the embryo, and an outer layer of trophoblast cells called the t ...

. When various parts of the trimer chains are knocked out by

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

s, devastating consequences occur in the

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

. If the β1 or γ1 chains of laminin-111 are absent the

basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...

fails to form. Without a basement membrane cells have nowhere to attach and all dependent activities such as

cell migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...

and epithelial formation can no longer occur. The self-assembly and tight network formation by laminin-111 are essential for holding the basement membrane together. Although it is expressed abundantly during the early embryonic stage, laminin-111 is mostly absent in adults. The injection of laminin-111, however, helps with

, a

neuromuscular disease A neuromuscular disease is any disease affecting the peripheral nervous system (PNS), the neuromuscular junction, or skeletal muscle, all of which are components of the motor unit. Damage to any of these structures can cause muscle atrophy and w ...

in which the connection between the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

and cell

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

is lost.Goudenege, S., Lamarre, Y., Dumont, N., Rousseau, J., Frenette , J., Skuk, D. and Tremblay, J.P. (2010). Laminin-111: A potential therapeutic agent for Duchenne muscular dystrophy. ''Molecular Therapy'', 18(12): 2155-2163. doi:10.1038/mt.2010.165.Rooney, J. E., Gurpur, P. B., & Burkin, D. J. (2009). Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy. ''Proceedings of the National Academy of Sciences'', 106(19): 7991-7996. Increased levels of laminin-111 triggered an increase in the expression of α7-integrin receptor and this prevented onset of the disease. Additionally, the presence of laminin-111 increased muscle strength and protected it from injury. When injected with

myoblast Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called ''myotubes''. In the early development of ...

transplants, laminin–111 decreased degeneration and inflammatory reactions and increased the success of the transplantation. The experiments utilizing laminin–111 as a source of therapy for Duchenne muscular dystrophy suggest that it has protective qualities in addition to its association with muscle tissue.

Mechanisms of action

Cell adhesion

cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...

laminin-111 and other isoforms are important

s that anchor cells to the

(ECM).Domogatskaya, An., Rodin, S., and Tryggvason, K. (2012). Functional diversity of laminins. ''Annual Review of Cell and Developmental Biology'', 28: 523-553. The linkage between cells and the ECM is formed by binding

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

s to one end of the laminin α chain and binding ECM components to another region of the laminin. Globular domains (G-Domain) of the α chain are the regions on laminin-111 that allow the binding of

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

s, sulfated glycolipids and

dystroglycan Dystroglycan is a protein that in humans is encoded by the ''DAG1'' gene. Dystroglycan is one of the dystrophin-associated glycoproteins, which is encoded by a 5.5 kb transcript in ''Homo sapiens'' on chromosome 3. There are two exons that are s ...

Cell signaling

Besides anchoring cells to the ECM, laminins are also involved in the signalling of cells and other components of the ECM. Even though there is not a general mechanism that applies to all laminins in signalling, there are some common pathways that can be seen in more than one isoform of laminin. For example, the PI3K/AKT pathway is used by laminin-111 (promotes cell-survival), 511 (prevents

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

with laminin 521), and 521 (stabilizes

pluripotency Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...

of human

embryonic stem cell Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consi ...

s). The pathway begins with the adhesion of the cell to the ECM for activation of the lipid-associated

PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

.Langenbach, K.J. and Rando, T.A. (2002). Inhibition of dystroglycan binding to laminin disrupts the PI3K/AKT pathway and cell-survival signalling in muscle cells. ''Muscle and Nerve'', 26: 644-653. Once PI3K is activated, it will localize

AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...

that is in the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

to the cell membrane where AKT is then

phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...

to promote cell survival.

Neurite outgrowth

When α chainsRialas, C. M., Nomizu, M., Patterson, M., Kleinman, H.K., Weston, C.A., and Weeks, B.S. (2000). Nitric Oxide mediates laminin-induced neurite outgrowth in PC12 cells. ''Experimental Cell Research'', 260(2): 268-276. of laminin-111 bind to cell surface receptors integrins α1β1, α3β1, α4β1, α6β1 and Cdc42

GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...

are activated.Weston, C.A., Anova, L., Rialas, C., Prives, J.M., and Weeks, B.S. (2000). Laminin-1 activates Cdc42 in the mechanism of laminin-1-mediated neurite outgrowth. ''Experimental Cell Research'', 260: 374-378. The activated GTPase then activates Cdc42 which further activates c-Jun kinases and phosphorylation of Jun. Activation of c-Jun kinases leads to high levels of

c-Jun Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only lat ...

expression which results in

neurite A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...

outgrowth.Dragunow, M., Xu, R., Walkton, M., Woodgate, A., Lawlor, P., MacGibbon, G.A., Young, D., Gibbons, H., Lipski, J., Muravlev, A., Pearson, A., and During, M. (2000). Thus, C-Jun promotes neurite outgrowth and survival in PC12 cells. ''Molecular Brain Research'', 83(1-2): 20-33. The synthesis of Nitric Oxides resides somewhere in the pathway and is yet to be determined. Weston et al. (2000) proposed that the synthesis of

Nitric Oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

may be upstream to the activation of Cdc42. Nonetheless, Nitric Oxide synthesis is shown to be an important element in laminin-mediated neurite outgrowth.

Future applications

Dynamic reciprocity theory

The dynamic reciprocity theory states that a cell’s fate depends on the exchange of chemical signals between the extracellular matrix and the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

of the cell.Schultz GS, Davidson JM, Kirsner RS, Bornstein P, Herman IM. (2011). Dynamic reciprocity in the wound microenvironment. ''Wound Repair Regen.'', 19: 134–148. Focussing on connections between laminin-111 and other proteins involved in cell-to-cell communication could spark further research that may help to further our current understanding of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

and how to slow down or stop its process.

Actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...

plays a role in nuclear activity which is an important process with regard to cell signalling influencing

cell differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...

and replication. It has been suggested that actin interactions directly influence

gene transcription Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...

as it interacts with

chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...

complexes as well as

RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the ...

s I, II and III.Zheng B, Han M, Bernier M, Wen JK. (2009). Nuclear actin and actin-binding proteins in the regulation of transcription and gene expression. ''FEBS J.'', 276: 2669–2685. However, the exact role that actin plays in transcription has not yet been determined.

Implications for cancer research

A group of distinguished scientistsSpencer VA, Costes S, Inman JL, Xu R, Chen J, Hendzel MJ, Bissell MJ. (2011). Depletion of nuclear actin is a key mediator of quiescence in epithelial cells. ''J Cell Sci.'', 124: 123–132. from the U.S. Department of Energy’s (DOE)

Lawrence Berkeley National Laboratory Lawrence Berkeley National Laboratory (LBNL), commonly referred to as the Berkeley Lab, is a United States Department of Energy National Labs, United States national laboratory that is owned by, and conducts scientific research on behalf of, t ...

(Berkeley Lab) did a recent study on how laminin-111 interacts with the

ic protein, actin. Their study gave the following conclusions: The biological process in which a cell ceases to continue growing and dividing is called

quiescence Quiescence (/kwiˈɛsəns/) is a state of quietness or inactivity. It may refer to: * Quiescence search, in game tree searching (adversarial search) in artificial intelligence, a quiescent state is one in which a game is considered stable and unl ...

(the opposite of cancer). ECM laminin-111 sends chemical signals that promotes adhesion of a cell and its ECM. Although the mechanism is unknown, these signals have also been linked to cell quiescence. Adding laminin-111 to breast

epithelial cell Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

s leads to quiescence by altering nuclear actin. High levels of laminin-111 deplete nuclear actin which induces quiescence of cells. However, when an isoform of actin, that cannot exit a cell’s nucleus, is active, cells continue to grow and divide even when laminin levels are high. ECM laminin-111 levels in a normal breast cell are significantly higher than laminin-111 levels in tissues of cancerous breast tissue. Simply increasing laminin levels in the ECM of cancerous breast cells is not enough to lead to quiescence. Therefore, it is implied that there are multiple factors working together influencing cell-to-cell communication. How laminin-111 and nuclear actin communicate is one of these factors. Laminin-111 could be the physiological regulator of nuclear actin which would suggest that depleting nuclear actin could be a key to achieving cell quiescence and returning to

homeostatic In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and i ...

operating conditions. Decreased expression of laminin-111 and the growth-inhibitory signals that it produces in

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

myoepithelial cell Myoepithelial cells (sometimes referred to as myoepithelium) are cells usually found in glandular epithelium as a thin layer above the basement membrane but generally beneath the luminal cells. These may be positive for alpha smooth muscle actin a ...

s begs for further investigation with regard to cancer research. Therefore, further exploration of laminin-111 and nuclear actin interaction could be a target for future experimental

therapeutic A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...

investigations.

References

{{Reflist Carbohydrate chemistry