Mothers against decapentaplegic homolog 4
Encyclopedia
SMAD family member 4, also known as SMAD4, is a protein
that in humans is encoded by the SMAD4 gene
.
SMAD4 is a 552-amino acid
protein involved in cell signaling
. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily. It binds receptor-regulated SMADs
such as SMAD1 and SMAD2, and forms a complex that binds to DNA and serves as a transcription factor
. It is the only known mammal
ian coSMAD. It is a homolog
of the Drosophila
protein: "Mothers against decapentaplegic
".
protein SMA. The name is a combination of the two. During Drosophila research, it was found that a mutation in the gene MAD in the mother repressed the gene decapentaplegic
in the embryo. The phrase "Mothers Bold textagainst" was added, since mothers often form organizations opposing various issues, e.g., Mothers Against Drunk Driving
(MADD).
specific binding properties, where it binds to specific nucleotide
sequences. It also facilitates the binding of SMAD4 to the phosphorylated C-terminus of R-SMAD
s. The MH2 domain is responsible for receptor recognition and oligomerization with other SMADs as well as DNA binding. The MH2 domain directly interacts with the MH1 domain of R-SMADs.
(R-SMADs), such as SMAD1 or SMAD2 and facilitates the translocation of the heteromeric complex into the nucleus
. SMAD4 may form heterotrimeric, heterohexameric or heterodimeric complexes with R-SMADs.
In the nucleus the heteromeric complex binds promoters and interact with transcriptional activators. SMAD3/SMAD4 complexes can directly bind the SBE (Smad-binding DNA element), which is a four-base-pair sequence 5′
-G
T
C
T
-3' or the complement 5′
-A
G
A
C
-3′
. These associations are weak and require additional transcription factor
s such as members of the AP-1
family, TFE3
and FoxG1
to regulate gene expression
.
Many TGFβ ligands use this pathway and subsequently SMAD4 is involved in many cell functions such as differentiation
, apoptosis
, gastrulation
, embryonic development and the cell cycle
.
(ECM). SMAD4 alterations have been found in multiploid colorectal cancer
and pancreatic carcinoma. It is found inactivated in at least 50% of pancreatic cancers. It is also found mutated in the autosomal dominant disease juvenile polyposis syndrome
(JPS). JPS is characterized by hamartomatous polyps in the gastrointestinal (GI) tract. These polyps are usually benign, however they are at greater risk of developing gastrointestinal cancers, in particular colon cancer.
Somatic mutations found in human cancers of the MH1 domain of Smad4 have been shown to inhibit the DNA-binding function of this domain.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the SMAD4 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
SMAD4 is a 552-amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
protein involved in cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily. It binds receptor-regulated SMADs
R-SMAD
R-SMAD stands for receptor-regulated SMAD. Smads are transcription factors that transduce extracellular TGF-ß superfamily ligand signaling from cell membrane bound TGF-ß receptors into the nucleus where they activate transcription TGF-ß target genes...
such as SMAD1 and SMAD2, and forms a complex that binds to DNA and serves as a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
. It is the only known mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian coSMAD. It is a homolog
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
of the Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
protein: "Mothers against decapentaplegic
Mothers against decapentaplegic
Mothers against decapentaplegic is a protein from the SMAD family that was discovered in Drosophila.The SMAD proteins are homologs of both the Drosophila protein "mothers against decapentaplegic" and the C. elegans protein SMA. The name is a combination of the two...
".
Nomenclature
The SMAD proteins are homologs of both the drosophila protein mothers against decapentaplegic (MAD) and the C. elegansCaenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
protein SMA. The name is a combination of the two. During Drosophila research, it was found that a mutation in the gene MAD in the mother repressed the gene decapentaplegic
Decapentaplegic
Decapentaplegic is a key morphogen involved in the development of the fruit fly Drosophila melanogaster. It is known to be necessary for the correct patterning of the fifteen imaginal discs, which are tissues that will become limbs and other organs and structures in the adult fly. It has also been...
in the embryo. The phrase "Mothers Bold textagainst" was added, since mothers often form organizations opposing various issues, e.g., Mothers Against Drunk Driving
Mothers Against Drunk Driving
Mothers Against Drunk Driving is a non-profit organization in the United States that seeks to stop drunk driving, support those affected by drunk driving, prevent underage drinking, and overall push for stricter alcohol policy...
(MADD).
Structure
SMADs are highly conserved across species, especially in the N terminal MH1 domain and the C terminal MH2 domain. The MH1 domain has DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
specific binding properties, where it binds to specific nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
sequences. It also facilitates the binding of SMAD4 to the phosphorylated C-terminus of R-SMAD
R-SMAD
R-SMAD stands for receptor-regulated SMAD. Smads are transcription factors that transduce extracellular TGF-ß superfamily ligand signaling from cell membrane bound TGF-ß receptors into the nucleus where they activate transcription TGF-ß target genes...
s. The MH2 domain is responsible for receptor recognition and oligomerization with other SMADs as well as DNA binding. The MH2 domain directly interacts with the MH1 domain of R-SMADs.
Function
SMAD4 binds to receptor-regulated SMADsR-SMAD
R-SMAD stands for receptor-regulated SMAD. Smads are transcription factors that transduce extracellular TGF-ß superfamily ligand signaling from cell membrane bound TGF-ß receptors into the nucleus where they activate transcription TGF-ß target genes...
(R-SMADs), such as SMAD1 or SMAD2 and facilitates the translocation of the heteromeric complex into the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
. SMAD4 may form heterotrimeric, heterohexameric or heterodimeric complexes with R-SMADs.
In the nucleus the heteromeric complex binds promoters and interact with transcriptional activators. SMAD3/SMAD4 complexes can directly bind the SBE (Smad-binding DNA element), which is a four-base-pair sequence 5′
Directionality (molecular biology)
Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. The chemical convention of naming carbon atoms in the nucleotide sugar-ring numerically gives rise to a 5′-end and a 3′-end...
-G
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
T
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
C
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
T
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
-3' or the complement 5′
Directionality (molecular biology)
Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. The chemical convention of naming carbon atoms in the nucleotide sugar-ring numerically gives rise to a 5′-end and a 3′-end...
-A
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
G
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
A
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
C
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
-3′
Directionality (molecular biology)
Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. The chemical convention of naming carbon atoms in the nucleotide sugar-ring numerically gives rise to a 5′-end and a 3′-end...
. These associations are weak and require additional transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s such as members of the AP-1
AP-1 (transcription factor)
In the field of molecular biology, the activator protein 1 is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors,...
family, TFE3
TFE3
Transcription factor E3 is a protein that in humans is encoded by the TFE3 gene.-Interactions:TFE3 has been shown to interact with E2F3, Mothers against decapentaplegic homolog 3 and Microphthalmia-associated transcription factor.-Further reading:...
and FoxG1
FOXG1
Forkhead box protein G1 is a protein that in humans is encoded by the FOXG1 gene....
to regulate gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
.
Many TGFβ ligands use this pathway and subsequently SMAD4 is involved in many cell functions such as differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, gastrulation
Gastrulation
Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a trilaminar structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.Gastrulation takes place after cleavage...
, embryonic development and the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
.
Mouse KO
In ovarian conditional mouse knockout of SMAD4, the granulosa cells undergo premature luteinization and express lower levels of follicle-stimulating hormone receptors (FSHR) and higher levels of luteinizing hormone receptors (LHR). This may be due in part to impairment of bone morphogenetic protein-7 effects as BMP-7 uses the SMAD4 signaling pathway.Disease
SMAD4, is often found mutated in many cancers. It acts as a tumor suppressor that functions in the regulation of the TGF-β signal transduction pathway, which negatively regulates growth of epithelial cells and the extracellular matrixExtracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM). SMAD4 alterations have been found in multiploid colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
and pancreatic carcinoma. It is found inactivated in at least 50% of pancreatic cancers. It is also found mutated in the autosomal dominant disease juvenile polyposis syndrome
Juvenile polyposis syndrome
Juvenile polyposis syndrome is a syndrome characterized by the appearance of multiple polyps in the gastrointestinal tract, usually in a child, adolescent or young adult. Polyps refers to a growth arising from the lumen of the colon or stomach...
(JPS). JPS is characterized by hamartomatous polyps in the gastrointestinal (GI) tract. These polyps are usually benign, however they are at greater risk of developing gastrointestinal cancers, in particular colon cancer.
Somatic mutations found in human cancers of the MH1 domain of Smad4 have been shown to inhibit the DNA-binding function of this domain.