WW and C2 domain containing 2 (WWC2) is a protein that in humans is encoded by the ''WWC2'' gene (4q35.1). Though function of WWC2 remains unknown, it has been predicted that WWC2 may play a role in cancer.

Gene

Locus The human gene WWC2 is found on

chromosome 4 Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the t ...

at band 4q35.1. The gene is found on the plus strand of the chromosome and is 8,822 base pairs long. The gene contains 23 exons. The WWC2 locus is quite complex and appears to produce several proteins with no sequence overlap Aliases A common alias of the gene is BH3-Only Member B (BOMB)

Homology

Paralogs There are two paralogs of WWC2 found in humans,

WWC1 Protein KIBRA also known as kidney and brain expressed protein (KIBRA) or WW domain-containing protein 1 (WWC1) is a protein that in humans is encoded by the ''WWC1'' gene. Research on human memory A single nucleotide polymorphism (rs1707014 ...

and WWC3.

is located on

chromosome 5 Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Ch ...

and is a probable regulator of the

Hippo signaling pathway The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its k ...

that plays a role in tumor suppression by restricting proliferation and promoting apoptosis. WWC3 is located on

chromosome X The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...

and not much is known about its function. Orthologs WWC2 is highly conserved in

Mammalia Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...

Aves Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

Reptilia Reptiles, as most commonly defined are the animals in the class Reptilia ( ), a paraphyletic grouping comprising all sauropsids except birds. Living reptiles comprise turtles, crocodilians, squamates (lizards and snakes) and rhynchocephalians ( ...

, and

Amphibia Amphibians are four-limbed and ectothermic vertebrates of the class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terrestrial, fossorial, arbore ...

, as well as the rare

coelacanth The coelacanths ( ) are fish belonging to the order Actinistia that includes two extant species in the genus ''Latimeria'': the West Indian Ocean coelacanth (''Latimeria chalumnae''), primarily found near the Comoro Islands off the east coast ...

, which is more closely related to lungfish, reptiles, and mammals than ray finned fish. WWC2 is conserved in some

Actinopterygii Actinopterygii (; ), members of which are known as ray-finned fishes, is a class of bony fish. They comprise over 50% of living vertebrate species. The ray-finned fishes are so called because their fins are webs of skin supported by bony or h ...

Gastropoda The gastropods (), commonly known as snails and slugs, belong to a large taxonomic class of invertebrates within the phylum Mollusca called Gastropoda (). This class comprises snails and slugs from saltwater, from freshwater, and from land. ...

, and

Bivalvia Bivalvia (), in previous centuries referred to as the Lamellibranchiata and Pelecypoda, is a class of marine and freshwater molluscs Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of w ...

. However, WWC2 is not well conserved in

Insecta Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three pairs o ...

Protein

Primary sequence The gene encodes a protein also called WWC2 which is 1,192 amino acids long. The molecular weight of the protein is 133.9 kilodaltons. The protein is serine rich with no charge clusters, hydrophobic segments or transmembrane domains. The isoelectric point is 5.23800 Domains and motifs WWC2 is a member of the WWC protein family which consists of a

WW domain The WW domain, (also known as the rsp5-domain or WWP repeating motif) is a modular protein domain that mediates specific interactions with protein ligands. This domain is found in a number of unrelated signaling and structural proteins and may be ...

and a

C2 domain A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 beta sheet, β-strands that co-ordinates two or three calcium ions, which bind in a cavity ...

. WWC2 contains two WW domains and one C2 domain. WWC2 also contains two domains of unknown function, DUF342 and DUF444. A

leucine zipper A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...

is located at position 854. Post translational modifications The WWC2 protein is predicted to be highly

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 ...

. There are 89 predicted sites of

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

phosphorylation, 17 predicted sites of

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...

phosphorylation, and 11 predicted sites of

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

phosphorylation. These numbers were relatively consistent in orthologous proteins. It is also predicted that

p38 mitogen-activated protein kinases p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differe ...

and

glycogen synthase kinase 3 Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen s ...

bind at position T3, and

casein kinase 2 Casein kinase 2 ()(CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumor ...

binds at positions S13 and T50.

Expression

Expression WWC2 is expressed at a low level, and is tissue specific to the uterus, thyroid, lung, and liver. WWC2 expression is found to be elevated 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 ...

and fetal stages of development. Transcript variants Many transcript variants exist for WWC2. Those that change a highly conserved amino acid residue, or surround a highly conserved amino acid residue are listed below:

Interacting proteins

Transcription factors Transcription factors with highest matrix scores that bind to sequences within the promoter (ID GXP_1499160) are shown below: * STAT (signal transducer and activator of transcription) * Muscle

TATA box In molecular biology, the TATA box (also called the Goldberg–Hogness box) is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has ...

* NOLF (neuron-specific olfactory factor) * XCPE (X gene core promoter element 1) *

CTCF Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the ''CTCF'' gene. CTCF is involved in many cellular processes, including transcriptional regulatio ...

(CCCTC-binding factor) * HDBP (

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

gene regulatory region) * OCT1 (octamer binding protein) * E2FF (

E2F E2F is a group of genes that encodes a family of transcription factors (TF) in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation a ...

myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...

activator cell cycle regulator) * ZF57 (KRAB domain zinc finger protein 57) * ZF07 (C2H2 zinc finger transcription factor 7) * EGRF (EGR/nerve growth factor induced protein) * CDEF (cell cycle dependent element - CDF-1 binding site) * AP2F (activator protein 2) Proteins Potential interacting proteins include:

YWHAZ 14-3-3 protein zeta/delta (14-3-3ζ) is a protein that in humans is encoded by the ''YWHAZ'' gene on chromosome 8. The protein encoded by this gene is a member of the 14-3-3 protein family and a central hub protein for many signal transduction pat ...

YWHAQ 14-3-3 protein theta is a protein that in humans is encoded by the ''YWHAQ'' gene. Function This gene product belongs to the 14-3-3 family of proteins that mediate signal transduction by binding to phosphoserine-containing proteins. This highly ...

RUVBL1 RuvB-like 1 (E. coli), also known as RUVBL1 and TIP49, is a human gene. RUVBL1 can form a hexamer. The hexamer can form a dodecamer with RUVBL2 protein. Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activ ...

, and

REPS1 RalBP1-associated Eps domain-containing protein 1 is a protein that in humans is encoded by the ''REPS1'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." ...

Clinical significance and Current bioinformation

While the exact function of WWC2 remains unknown, several mutations and variants of WWC2 have been researched in disease. A novel

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

in WWC2 was analyzed in

Restless Leg Syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...

, but was not identified as a candidate gene. One study examined the role of Drosophila

KIBRA Protein KIBRA also known as kidney and brain expressed protein (KIBRA) or WW domain-containing protein 1 (WWC1) is a protein that in humans is encoded by the ''WWC1'' gene. Research on human memory A single nucleotide polymorphism (rs1707014 ...

(WWC1) in the Expanded-Hippo-Warts signaling cascade, which is involved with

tumor suppression A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...

. The study stated that copy number aberration, translocation, and point mutations of WWC2, as well as other genes, should be further investigated in human cancers. WWC2 alias, BOMB, was researched in a grant suggesting that BOMB, along with two other genes ( APOL6 and

APOL1 Apolipoprotein L1 is a protein that in humans is encoded by the ''APOL1'' gene. Two transcript variants encoding two different isoforms have been found for this gene. Species distribution This gene is found only in humans, African green monkeys ...

) promoted cell death in

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

-null

HCT116 cells HCT116 is a human colon cancer cell line used in therapeutic research and drug screenings. Characteristics HCT116 cells have a mutation in codon 13 of the KRAS proto-oncogene, and are suitable transfection targets for gene therapy research. The ...

References

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