Zinc transporter ZIP9, also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''SLC39A9''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. This protein is the 9th member out of 14 ZIP family proteins, which is a

membrane androgen receptor Membrane androgen receptors (mARs) are a group of G protein-coupled receptors (GPCRs), which bind and are activated by testosterone and/or other androgens. Unlike the androgen receptor (AR), a nuclear receptor which mediates its effects via genomic ...

(mAR)

coupled ''Coupled'' is an American dating game show that aired on Fox from May 17 to August 2, 2016. It was hosted by television personality, Terrence J and created by Mark Burnett, of '' Survivor'', '' The Apprentice'', '' Are You Smarter than a 5th ...

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

s, and also classified as a

zinc transporter protein Zinc transporter proteins (Zrt), or simply zinc transporters, are membrane transport proteins of the solute carrier family which control the membrane transport of zinc and regulate its intracellular and cytoplasmic concentrations. They include two m ...

. ZIP family proteins

transport Transport (in British English) or transportation (in American English) is the intentional Motion, movement of humans, animals, and cargo, goods from one location to another. Mode of transport, Modes of transport include aviation, air, land tr ...

zinc metal from the

extracellular environment This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

into

cells Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...

through

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

Classification and nomenclature

Mammalian cells have two major groups of

s; the ones that export zinc from the

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

to the

extracellular space Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells. The composit ...

( efflux), which are called ZnT (SLC30 family), and ZIP (SLC39 family) proteins whose functions are in the opposite direction ( influx). ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to Zrt and Irt proteins which are respectively

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

and

iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...

-regulated transporter proteins in

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...

and

Arabidopsis ''Arabidopsis'' (rockcress) is a genus in the family Brassicaceae. They are small flowering plants related to cabbage and mustard. This genus is of great interest since it contains thale cress (''Arabidopsis thaliana''), one of the model organ ...

that were discovered earlier than ZIP and ZnT proteins. ZIP family consists of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of subfamily I.

Isoforms

ZIP9 can be present as 3 different

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

in human

. The canonical

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

of this protein has a length of 307

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

, with a

molecular mass The molecular mass () is the mass of a given molecule, often expressed in units of daltons (Da). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The derived quan ...

of . In the second isoform, amino acids 135-157 are missing, so its length and

molecular weight A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

are respectively reduced to 284 amino acids and . In the third isoform the amino acids 233-307 are missing, so the isoform only has 232 amino acids and its molecular mass is . Additionally, the last amino acid of isoform 3, which is usually

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 − ...

, is replaced with

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...

Discovery

ZIP9

was first discovered in Atlantic croaker (''Micropogonias undulatus)''

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

ovary The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...

and

testicular A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The r ...

tissues and named "AR2" in 1999, together with another

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

which was found only in brain tissue, and it was named "AR1" in that time. AR1 and AR2 were first thought to be nuclear androgen receptors (nAR), however, further studies on their

biochemical Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, ...

and functional features in 2003 illustrated that they were involved in non-genomic mechanisms in the

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

of the cells and were

s. In 2005, the similarities between the

nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

and amino acid

sequences In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is call ...

of AR2 and ZIP family proteins were discovered in other

vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

s, suggesting that AR2 is from this family of proteins. A study in 2014 utilised the latest research technologies to clone and

express Express, The Expresss or EXPRESS may refer to: Arts, entertainment and media Film * ''Express: Aisle to Glory'', a 1998 comedy short film featuring Kal Penn * ''The Express: The Ernie Davis Story'', a 2008 film starring Dennis Quaid * The Expre ...

a particular

cDNA In genetics, complementary DNA (cDNA) is DNA that was reverse transcribed (via reverse transcriptase) from an RNA (e.g., messenger RNA or microRNA). cDNA exists in both single-stranded and double-stranded forms and in both natural and engin ...

of the female Atlantic croaker ovaries, which

encoded In communications and information processing, code is a system of rules to convert information—such as a letter, word, sound, image, or gesture—into another form, sometimes shortened or secret, for communication through a communication ...

a protein showing the characteristics of the canonical isoform of ZIP9, as a novel membrane androgen receptor(mAR). PDB 1hzx 7TM Sketch Membrane

Structure

Unlike other ZIP subfamilies that are consisted of 8 transmembrane (TM) domains with an

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

, ZIP9 consists of a 7 TM structure with an

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

C-terminus. ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular loop, it contains

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

-rich clusters. ZIP9 and other ZIP proteins have

polar Polar may refer to: Geography * Geographical pole, either of the two points on Earth where its axis of rotation intersects its surface ** Polar climate, the climate common in polar regions ** Polar regions of Earth, locations within the polar circ ...

or charged amino acids in their TM domains which probably play important roles in making ion transfer channels and therefore in importing zinc ions into cytoplasm.

Location, expression and function

ZIP9 influxes zinc ions into the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

and its gene is expressed almost in every tissue of human body. The sub-cellular location of ZIP9 is in plasma,

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 Nucleu ...

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

and

mitochondrial membrane A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

. One of the responsibilities of ZIP9 is the

homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...

in th
secretory pathway
during which this protein stays within the Trans Golgi Network regardless of the change in the

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'', ...

s of zinc. ZIP9 is the only ZIP protein that

signals A signal is both the process and the result of Signal transmission, transmission of data over some transmission media, media accomplished by embedding some variation. Signals are important in multiple subject fields including signal processin ...

through

binding, and pharmaceutical agents decrease its ligand binding once ZIP9 is uncoupled from G proteins. ZIP9 is also the only member of ZIP family with mAR characteristics.

Ligands

Testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

has high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for ZIP9 with a K_d of 14 nM and acts as an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the receptor. In contrast, the other

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

(DHT) and

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroe ...

show low

for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

at sufficiently high concentrations. Moreover, the

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

androgens mibolerone and

metribolone Metribolone (developmental code R1881, also known as methyltrienolone) is a synthetic and orally active anabolic–androgenic steroid (AAS) and a 17α-alkylated nandrolone (19-nortestosterone) derivative which was never marketed for medical use ...

(R-1881), the endogenous androgen 11-ketotestoterone, and the other

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wit ...

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

and

cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...

are all ineffective competitors for the receptor. Since mibolerone and metribolone bind to and activate the nuclear

(AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone. The

nonsteroidal antiandrogen A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens lik ...

bicalutamide Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...

has been identified as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.

Clinical significance

Zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

is very important in human health, because zinc is present in the

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

of some proteins like zinc-dependent

metalloenzymes Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains al ...

and zinc-finger-containing transcriptional factors. In addition, zinc is involved in

signalling A signal is both the process and the result of transmission of data over some media accomplished by embedding some variation. Signals are important in multiple subject fields including signal processing, information theory and biology. In ...

for

cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

, proliferation, division and

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. As a result, any dysfunction of

s can be harmful for the cells, and some of them are associated with different

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

and

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. For instance, through activation of ZIP9,

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

has been found to increase

levels in

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

, and

ovarian follicle An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. In humans, women have approximately 200,000 to 300,000 follicles at the time of puberty, ea ...

cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

s and to induce

in these cells, an action which may be mediated partially or fully by increased zinc concentrations.

Gene mutations

Mutations 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, mitosi ...

in the SLC39A9 gene can occur due to

genetic deletion In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA replication. Any number of nucleoti ...

of the q24.1-24.3 band of base pairs within the human chromosome 14. This interstitial deletion

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, ...

deletes the SLC39A9 gene along with 18 other genes found close to the SLC39A9 gene on chromosome 14 Although specific gene associated diseases have not been determined, the deletion of this band causes diseases such as

congenital heart defects A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital h ...

, mild

intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

brachydactyly Brachydactyly () is a medical term denoting the presence of abnormally short digits (fingers or toes) at birth. The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an inherited, dominant t ...

, and all patients with band deletion had

hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition, the distance between the inner eye corners, a ...

and a broad

nasal bridge The nasal bridge is the upper part of the nose, where the nasal bones and surrounding soft tissues provide structural support. While commonly discussed in human anatomy, nasal bridges exist in various forms across many vertebrates, particularl ...

. Patient specific clinical issues included ectopic organs, undescended testes, also called

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is . It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boy ...

, and malrotation of the small intestine. Deletion mutation involving the SLC39A9 gene has also been reported in 23 cases of patients with circulation related cancers such as

B-cell lymphoma The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are Tumors of the hematopoietic and lymphoid tissues, "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals. ...

and

B-cell chronic lymphocytic leukaemia B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

(CLL). Chimeric genes are a result of faulty

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...

, and arise when two or more coding sequences of the same or different chromosome combine in order to produce a single new gene. SLC39A9 forms a

chimeric gene Chimeric genes (literally, made of parts from different sources) form through the combination of portions of two or more coding sequences to produce new genes. These mutations are distinct from fusion genes which merge whole gene sequences into ...

product with a gene called PLEKHD1, that codes for an intracellular protein found within the

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

. A study done in Seattle, USA, established the presence of the fusion protein product of the SLC39A9-PLEKHD1 gene to be present in 124 cases of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

and was closely related to the pathophysiology of disease. The fusion protein had features from both the parent genes and also possessed the ability to interact with cellular signalling pathways involving kinases such as

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, tra ...

and Erk, leading to their increased phosphorylation within the brain and a consequent onset of schizophrenia. SLC39A9 gene also forms a fusion transcript with another gene called MAP3K9, that encodes for MAP3 kinase enzyme. This SLC39A9-MAP3K9 fusion gene has a repetitive occurrence in breast cancers, demonstrated by a study done on 120 primary breast cancer samples from Korean women in 2015.

Cancer

Breast and prostate

A study in 2014, elucidated the intermediary role of ZIP9 in causing human

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

and

, as it induced the

in the presence of testosterone in breast and prostate cancerous cells. unlike ZIP1, 2 and 3, ZIP9

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

expression was increased in human prostate and breast

malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...

cancer cells, which probably was because cells that divide rapidly require more zinc.

Brain

Treatment of glioblastoma cells with

TPEN TPEN (''N'',''N'',','-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine) is an intracellular membrane-permeable ion chelator. TPEN has a high affinity for many transition metals and should not be considered specific or selective for a particular ion. ...

showed that

upregulation In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as R ...

of ZIP9 in glioblastoma cells enhances

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

brain cancer A brain tumor (sometimes referred to as brain cancer) occurs when a group of cells within the brain turn cancerous and grow out of control, creating a mass. There are two main types of tumors: malignant (cancerous) tumors and benign (non-cance ...

by influencing

P53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...

and GSK-3ß, and also ERK and

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, tra ...

signalling pathways Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term ...

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

after

activation In chemistry and biology, activation is the process whereby something is prepared or excited for a subsequent reaction. Chemistry In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical or ...

B-cell receptor The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 Transmembrane protein, transmemb ...

Diabetes

Zinc must be constantly supplied to Pancreatic β-cells to function normally and maintain glycaemic control. The insulin secretory pathway in humans is highly dependent on zinc activities. The cells lose many zinc ions during the secretion of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

, and need to receive more zinc, and expression of ZIP9

during this process increases. As a result, ZIP9, which is involved in importing zinc into the cells, is potentially a target for therapeutic studies in the future regarding diabetes type2.

References

{{Androgen receptor modulators G protein-coupled receptors Solute carrier family