Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed
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 ...
that in humans is encoded by the ''IQGAP1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
IQGAP1 is a
scaffold protein
In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them in ...
involved in regulating various cellular processes ranging from organization of the
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 ...
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 ...
, transcription, and
cellular 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 indire ...
to regulating the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
.
History
IQGAP1 was discovered in 1994.
Its name stems from the fact that its RasGAP-related domain (GRD) has sequence homology to the
Sar1 GTPase.
It was hypothesized that IQGAP1 would act as a
GTPase activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are ...
(GAP) protein, promoting the switch of
ras GTPases from the active GTP to GDP-bound forms. However, despite the homology of IQGAP’s GAP domain to sar1 and the fact that IQGAP1 binds Rho GTPases Rac1 and Cdc42, IQGAP does not actually have GAP function. Instead, it binds the active (GTP-bound) forms of
RAC1 and
CDC42 with higher affinity than GDP-bound forms, and stabilizes the active form in vivo.
IQGAP1 is now recognized as a protein scaffold that integrates signals regulating
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 ...
,
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 ...
cytoskeleton, the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
,
and other cellular functions. IQGAP is particularly interesting as a therapeutic target since it acts as a node for so many signaling pathways implicated in
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 ...
progression.
Expression
Analysis of IQGAP1 expression in human tissues has indicated that the scaffold is more or less ubiquitously expressed.
It is usually found in 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 ...
,
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
, and
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 ...
. In other words it is found throughout the cell as well as throughout tissue types. Expression analysis has also indicated that IQGAP1 is overexpressed in many cancers, and in more aggressive colorectal and ovarian cancers, IQGAP1 is localized at the invasive front of the neoplasm, indicating a role in mobilization of the cells.
Importantly, approximately 10% of genes that show increased expression in
metastatic
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
cells are IQGAP1 binding partners.
Domains
IQGAP1 is a 190 kDa protein with 5 domains.
A
protein domain
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...
is a subsection of a protein that shows up multiple times in biology and can exist independently of the surrounding protein. It is very similar to subsections of other proteins, and could be cut out of the current protein, exist and function by itself, or be pasted in to a new protein strand and still function properly. Since this area of the protein is conserved in amino acid sequence and structure, it can be characterized by function or binding partner. IQGAP1 has 5 well-known domains separated by other amino acids.
Starting at the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
(or front of the protein), IQGAP1 contains a
calponin homology domain
Calponin homology domain (or CH domain) is a family of actin binding domains found in both cytoskeletal proteins and signal transduction proteins. The domain is about 100 amino acids in length and is composed of four alpha helices. It comprise ...
(CHD), which mediates actin-binding
and binds
calponin
Calponin is a calcium binding protein. Calponin tonically inhibits the ATPase activity of myosin in smooth muscle. Phosphorylation of calponin by a protein kinase, which is dependent upon calcium binding to calmodulin, releases the calponin's ...
.
The WW, or
poly-proline protein-protein domain, so named because of two functionally conserved tryptophans, W, is a protein-protein interaction domain that associates with proline-rich regions of other proteins.
The
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 ...
is followed by 4
IQ motifs which form an IQ domain. This domain binds
calmodulin
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...
,
a protein known as a calcium sensor that can bind and regulate many target proteins.
A GRD (rasGAP-related domain) follows the IQ domain. This domain is highly similar to the functional subunit of
Ras
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
GTPase-activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are a ...
s (GAPs) and was thus thought to have GAP function. IQGAP1 does bind
Rho GTPases
Rho GTPase may refer to:
*Any member of the Rho family of GTPases
*The members of the Rho family of GTPases belonging to the '' Rho subclass''
*RHOA
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase p ...
CDC42 and
RAC1, however, IQGAP1 is unusual in that it actually has no GAP function, and instead stabilizes the GTP-bound proteins in their active state.
Finally, IQGAP1 has a RasGAP_c carboxy terminal sequence important for binding
Beta-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...
and
E-cadherin
Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian ...
.
Related Proteins
Homologues of IQGAP1 are known in species as divergent as yeast, worms, and humans (as well as other mammals), though the domains are not always highly conserved.
IQGAP1 is the most well studied member of the IQGAP family of scaffold proteins. The two other members of the family include
IQGAP2
Ras GTPase-activating-like protein IQGAP2 is an enzyme that in humans is encoded by the ''IQGAP2'' gene.
Function
This gene encodes a member of the IQGAP family. The protein contains three IQ domains, one calponin homology domain, one Ras-GAP ...
and
IQGAP3 which have far more restricted expression patterns in comparison with IQGAP1. IQGAP2 is found in the liver, stomach, and platelets and is 62% identical to IQGAP1,
but appears to have a drastically divergent function in terms of pathology.
In the brain, IQGAP3 appears to play an important role in neuronal morphogenesis.
Function
This gene encodes a member of the
IQGAP IQ motif containing GTPase activating protein (IQGAP) is a carrier protein.
It is associated with the Rho GTP-binding protein.
Genes
* IQGAP1
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed prote ...
family. The protein contains four
IQ domains, one
calponin homology domain
Calponin homology domain (or CH domain) is a family of actin binding domains found in both cytoskeletal proteins and signal transduction proteins. The domain is about 100 amino acids in length and is composed of four alpha helices. It comprise ...
, one
Ras-GAP domain and one
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 ...
. It interacts with components of the
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 ...
such as the formin Dia1 (
mDia1
mDia1 (also known as Dia1, Drf1 for Diaphanous-related formin-1, Diaph1, KIAA4062, p140mDia, mKIAA4062, or D18Wsu154e) is a member of the protein family called the formins and is a Rho effector. It is the mouse version of the diaphanous homolog 1 ...
),
with cell adhesion molecules (
CAMs), and with several signaling molecules to regulate cell
morphology
Morphology, from the Greek and meaning "study of shape", may refer to:
Disciplines
* Morphology (archaeology), study of the shapes or forms of artifacts
* Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies ...
and
motility
Motility is the ability of an organism to move independently, using metabolic energy.
Definitions
Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
. For example, IQGAP1 expression is necessary for neuronal process outgrowth on the cell adhesion molecule PTPmu (
PTPRM
Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the ''PTPRM'' gene.
Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases a ...
).
Expression of the protein is upregulated by gene amplification in two
gastric cancer
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
cell lines
and its over-expression and distinct membrane localisation is also observed in a range of tumours.
Interactions
IQGAP1 is a node intersected by many signaling pathways. As such it has many binding partners, many of which have essential roles in control of the cell cycle and actin cytoskeleton.
IQGAP1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
Calmodulin 1
Calmodulin 1 is a protein that in humans is encoded by the ''CALM1'' gene.
Function
Calmodulin 1 is the archetype of the family of calcium-modulated (calmodulin) proteins of which nearly 20 members have been found. They are identified by their ...
,
*
CDC42,
* CDH1,
* CLIP1
CAP-GLY domain containing linker protein 1, also known as CLIP1, is a protein which in humans is encoded by the ''CLIP1'' gene.
Interactions
CLIP1 has been shown to interact with IQGAP1, Mammalian target of rapamycin and PAFAH1B1
Platelet-act ...
,
* PRKACA
The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the ''PRKACA'' gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catal ...
,
* RAC1,[ and
* ]S100B
S100 calcium-binding protein B (S100B) is a protein of the S-100 protein family.
S100 proteins are localized in the cytoplasm and nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cyc ...
.
*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 ...
– cytoskeletal structure
*ARF6
ADP-ribosylation factor 6 (ARF6) is a member of the ADP ribosylation factor family of GTP-binding proteins. ARF6 has a variety of cellular functions that are frequently involved in trafficking of biological membranes and transmembrane protein ...
* APC
*Beta-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...
–cell adhesion and WNT signaling: transcription
* B-raf – MAPK pathway
*CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhesi ...
*Erk1/2 – MAPK pathway, cell cycle control, proliferation
*Mek ½ -- MAPK pathway, cell cycle control, proliferation
* Src
*PTPmu (PTPRM
Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the ''PTPRM'' gene.
Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases a ...
)
*complete list at
Function as a Scaffold
Protein binding does not by itself construct an interesting story. Far more important is the outcome of the binding event. Does binding change the target protein’s localization? Does it activate the target, or in some way change the target (or effector molecule’s) conformation? As a scaffolding protein
In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them in ...
, IQGAP1 binds and regulates many targets—its role is to integrate and mediate signaling from diverse pathways and insulate key pathway members from crosstalk
In electronics, crosstalk is any phenomenon by which a signal transmitted on one circuit or channel of a transmission system creates an undesired effect in another circuit or channel. Crosstalk is usually caused by undesired capacitive, induc ...
.
Scaffolds organize signaling pathways
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
—help regulate how various extracellular signals can be transduced by the same canonical pathway members into various cellular outputs. Generally, scaffolds regulate output, localization, and selectivity of pathways.
As a scaffold involved in different signaling pathways (actin 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 ...
, cellular 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 indire ...
, cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
, transcription), IQGAP1 has a unique ability to potentially couple diverse cellular functions. For example IQGAP1 is associated with actin dynamics through direct binding of actin and indirect regulation via Cdc42/Rac1, but also modulates the MAPK pathway
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
which is associated with cell cycle control. Thus IQGAP1 may couple MAPK signaling (decisions about cell fate Within the field of developmental biology, one goal is to understand how a particular cell develops into a final cell type, known as fate determination. Within an embryo, several processes play out at the cellular and tissue level to create an organ ...
) to the cytoskeleton or cellular adhesion (potentially acting out those decisions)—an important implication for cancer.
To simplify, due to its diverse range of binding partners, IQGAP1 may act as a link between logically related but molecularly distinct cellular functions. In the above example, actin cytoskeleton rearrangement is required for proliferation (cytokinesis
Cytokinesis () is the part of the cell division process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and meios ...
during mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
). IQGAP1 helps cells both listen to and act on signals, playing an integral role in connecting the dots between signals for proliferation and the actual cellular response.
Key pathways
ERK MAPK
The Ras
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
→Raf
The Royal Air Force (RAF) is the United Kingdom's air and space force. It was formed towards the end of the First World War on 1 April 1918, becoming the first independent air force in the world, by regrouping the Royal Flying Corps (RFC) and ...
→ MEK→ ERK MAPK signaling pathway plays an integral part in the processes of cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
, differentiation, and 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 ...
. This pathway is conserved across all eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s.
Various extracellular signals induce the ERK MAPK pathway including EGF, IGF-1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.
IGF-1 is a protein that in humans is ...
, PDGF
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
, and NGF. The various scaffolds of this pathway, including IQGAP1, are responsible for modulating the cellular response to the activity of this pathway. For instance, in a given cell line, activation by one extracellular signal may induce differentiation but not proliferation, while activation of the same ERK MAPK pathway by a different extracellular signal will induce proliferation but not differentiation. IQGAP1 seems to be responsible for the specific output of the pathway upon activation by EGF.
IQGAP1 plays a significant role in the propagation of this MAPK signaling pathway. IQGAP directly binds b-RAF, MEK1/2 and ERK1/2, and is in fact necessary for the phosphorylation (activation) of ERK upon stimulation by EGF.
Cytoskeletal control (actin dynamics)
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 ...
is a major building block of every eukaryotic cell’s cytoskeleton. Actin dynamics play a major role in cell motility
Motility is the ability of an organism to move independently, using metabolic energy.
Definitions
Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
(filaments are built at the leading edge of a moving cell and deconstructed at the receding edge). IQGAP1 binds actin and influences actin dynamics by localizing to the leading edge and recruiting actin polymerization machinery.
IQGAP1 binds and is a target of the Rho GTPases CDC42 and RAC1 which are well known regulators of the actin cytoskeleton. Despite its name, IQGAP1 does not have GAP function, and instead stabilizes active Cdc42. This increase in a local pool of active Cdc42 stimulates 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 ...
filament formation and thus filopodia
Filopodia (singular filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lame ...
formation.
IQGAP1 can crosslink actin, and in many organisms, IQGAP1 is involved in cytokinesis
Cytokinesis () is the part of the cell division process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and meios ...
.
Adhesion
Cadherins
Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...
are a family of adhesion proteins that localize to the cell surface where they anchor a cell to its neighbors by clasping on to the extracellular portion of the neighbor’s cadherins. 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 ...
binds a-catenin which binds beta-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...
which in turn binds E-cadherin
Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian ...
. E-cadherin juts into the extracellular space to grasp the extracellular domains of neighboring E-cadherins. IQGAP1 localizes to cell-cell contacts and binds actin, b-catenin, and E-cadherin, weakening these junctions and thus decreasing cell-cell adhesion. IQGAP weakens cell adhesion by displacing a-catenin from the complex.
Active RAC1 binds IQGAP1 to crosslink actin filaments and prevents IQGAP1 from interacting with beta-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...
, stabilizing cell-cell contacts. When IQGAP1 does not bind Rac1, however, it binds beta-catenin, displacing a-catenin from the cadherin-catenin cellular adhesion complex.
Transcription
IQGAP1 also affects transcription through the Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
by its interaction with beta-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...
. Beta-catenin is usually sequestered in a complex and excluded from the nucleus, but upon WNT activation this complex is broken and beta-catenin translocates to the nucleus where it activates transcriptional programs. IQGAP1 binds b-catenin and increases nuclear localization and expression of beta-catenin’s transcriptional targets.
Clinical significance
IQGAP1 is associated with cytoskeletal
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 compo ...
dynamics, transcription, 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 ...
, cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
, and morphology
Morphology, from the Greek and meaning "study of shape", may refer to:
Disciplines
* Morphology (archaeology), study of the shapes or forms of artifacts
* Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies ...
, all of which are disrupted in 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 ...
. As a modulatory protein intersecting all of these pathways, IQGAP1 can couple many of them, and is also responsible for their proper propagation. Since cancer is a disease characterized by the perturbation of many of these cellular processes, IQGAP1 is a logical oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. candidate and therapeutic target.
Expression analysis has implicated IQGAP1 in colorectal
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...
, squamous 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 ...
, breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and secret ...
, gastric
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
, 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 ...
, lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
, and ovarian
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 ...
cancers,[ Human protein atlas: http://www.proteinatlas.org/ENSG00000140575] and in some of these cancers, higher IQGAP1 expression levels indicate a poor prognosis.
In order for a cancer to metastasize
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
, cells must gain migratory abilities and invade other tissues. Through Rac1/CDC42, IQGAP1 regulates cellular adhesion and actin dynamics.
In normal cells IQGAP1 localizes to areas of high actin turnover. This characteristic is echoed in invasive tissues, where IQGAP1 localizes to the leading edge of migrating cells. Over-expression of IQGAP1 was associated with increased migration and invasion in a human breast epithelial cancer cell line (MCF-7
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old White woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-wor ...
cells). IQGAP1 may also be involved in the deregulation of proliferation and differentiation through its modulation of the ERK MAPK pathway.
IQGAP1 may be necessary for tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
. IQGAP1 knockdown in MCF-7 cancer cells reduced the 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 ...
phenotype (serum-dependent proliferation and anchorage independent growth). 100% of mice injected with MCF-7 cells overexpressing IQGAP1 developed tumors and these tumors were highly invasive. Control MCF-7 cells formed tumors in 60% of the mice, and MCF-7 cells with stable knockdown of IQGAP1 only formed tumors 20% of the time. The mechanism for how IQGAP1 may modulate tumorigenesis/invasion through its various binding partners is of great interest.
IQGAP1 null mice appear significantly normal, with the only life history abnormality being an increase in gastric hyperplasia
Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferati ...
. Thus, IQGAP1 may be an effective therapeutic target, if its knockdown has little effect in 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 ...
tissue but its expression is important in cancer.
References
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