Cortactin
Encyclopedia
Cortactin is a monomeric protein
located in the cytoplasm
of cells that can be activated by external stimuli to promote polymerization
and rearrangement of the actin
cytoskeleton
, especially the actin cortex around the cellular periphery. It is present in all cell types. When activated, it will recruit Arp2/3 complex
proteins to existing actin microfilaments, facilitating and stabilizing nucleation
sites for actin branching. Cortactin is important in promoting lamellipodia
formation, invadopodia
formation, cell migration
, and endocytosis
.
that consists of an amino-terminal acidic (NTA) region; 37-residue-long segments that are highly conserved among cortactin proteins of all species and repeated up to 6.5 times in tandem (“cortactin repeats”); a proline-rich region; and an SH3 domain
. This basic structure is highly conserved among all species that express cortactin.
, by tyrosine kinases or serine/threonine kinases, in response to extracellular signals like growth factors, adhesion sites
, or pathogenic invasion of the epithelial layer.
The SH2 domain
of certain tyrosine kinases, such as the oncogene Src
kinase, binds to cortactin’s proline-rich region and phosphorylates it on Tyr421, Tyr466, and Tyr482. Once activated in this way, it can bind to filamentous
actin (F-actin) with the fourth of its cortactin repeats. As the concentration of phosphorylated cortactin increases in specific regions within the cell, the monomers each begin to recruit an Arp2/3 complex to F-actin. It binds to Arp2/3 with an aspartic acid-aspartic acid-tryptophan (DDW) sequence in its NTA region, a motif that is often seen in other actin nucleation-promoting factors (NPFs).
Certain serine/threonine kinases, such as ERK
, can phosphorylate cortactin on Ser405 and Ser418 in the SH3 domain. Activated like this, it still associates with Arp2/3 and F-actin, but will also allow other actin NPFs, most importantly N-WASp (Neuronal Wiskott-Aldrich syndrome protein
), to bind to the complex as well; when phosphorylated by tyrosine kinases, other NPFs are excluded. The ability of these other NPFs to bind the Arp2/3 complex while cortactin is also bound could come from new interactions with cortactin’s SH3 domain, which is in a different conformation when phosphorylated by Ser/Thr kinases and thus may be more open to interactions with other NPFs. Having other NPFs bind to the Arp2/3 complex at the same time as cortactin may enhance nucleation site stability.
Cortactin is very active in lamellipodia, protrusions of the cell membrane formed by actin polymerization and treadmilling
that propel the cell along a surface as it migrates towards some target.
Cortactin acts as a link between extracellular signals and lamellipodial “steering.” When a receptor tyrosine kinase
on the cell membrane
binds to an adhesion site, for example, cortactin will be phosphorylated locally to the area of binding, activate and recruit Arp2/3 to the actin cortex in that region, and thus stimulate cortical actin polymerization and movement of the cell in that direction. Macrophages, highly mobile immune cells that engulf cellular debris and pathogens, are propelled by lamellipodia and identify/migrate toward a target via chemotaxis
; thus, cortactin must also be activated by receptor kinases that pick up a large variety of chemical signals.
Studies have implicated cortactin in both clathrin
-mediated endocytosis and clathrin-independent endocytosis. In both kinds of endocytosis, it has long been known that actin localizes to sites of vesicle invagination and is a vital part of the endocytic pathway, but the actual mechanisms by which actin facilitates endocytosis are still unclear. Recently, however, it has been found that dynamin
, the protein responsible for breaking the newly formed vesicular bud off the inside of the plasma membrane, can associate with the SH3 domain of cortactin. Since cortactin recruits the Arp2/3 complexes that lead to actin polymerization, this suggests that it may play an important part in linking vesicle formation to the as yet unknown functions actin has in endocytosis.
with WIPF1
, KCNA2
, FER
, CTNND1
, SHANK2
, ARPC2
, ACTR3
and WASL
.
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...
located in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
of cells that can be activated by external stimuli to promote polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...
and rearrangement of the actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
, especially the actin cortex around the cellular periphery. It is present in all cell types. When activated, it will recruit Arp2/3 complex
Arp2/3 complex
Arp2/3 complex is a seven-subunit protein that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the actin cytoskeleton and is found in most in actin cytoskeleton-containing eukaryotic cells....
proteins to existing actin microfilaments, facilitating and stabilizing nucleation
Nucleation
Nucleation is the extremely localized budding of a distinct thermodynamic phase. Some examples of phases that may form by way of nucleation in liquids are gaseous bubbles, crystals or glassy regions. Creation of liquid droplets in saturated vapor is also characterized by nucleation...
sites for actin branching. Cortactin is important in promoting lamellipodia
Lamellipodia
The lamellipodium is a cytoskeletal protein actin projection on the mobile edge of the cell. It contains a quasi-two-dimensional actin mesh; the whole structure propels the cell across a substrate...
formation, invadopodia
Invadopodia
Invadopodia or invasive feet are protrusions in the cell membrane of some cells that are rich in actin and extend into the extracellular matrix . Researchers have reported that invadopodia formation is initiated with the assembly of actin core structures, followed by the accumulation of mtrix...
formation, cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
, and endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
.
Structure
Cortactin is a thin, elongated monomerMonomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
that consists of an amino-terminal acidic (NTA) region; 37-residue-long segments that are highly conserved among cortactin proteins of all species and repeated up to 6.5 times in tandem (“cortactin repeats”); a proline-rich region; and an SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
. This basic structure is highly conserved among all species that express cortactin.
Activation and binding
Cortactin is activated via phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, by tyrosine kinases or serine/threonine kinases, in response to extracellular signals like growth factors, adhesion sites
Focal adhesion
In cell biology, focal adhesions are specific types of large macromolecular assemblies through which both mechanical force and regulatory signals are transmitted. More precisely, they can be considered as sub-cellular macromolecules that mediate the regulatory effects In cell biology, focal...
, or pathogenic invasion of the epithelial layer.
The SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
of certain tyrosine kinases, such as the oncogene Src
Src
Src may refer to:* Src , a family of proto-oncogenic tyrosine kinases* In computer programming, a common abbreviation for source codeSee also*SRC...
kinase, binds to cortactin’s proline-rich region and phosphorylates it on Tyr421, Tyr466, and Tyr482. Once activated in this way, it can bind to filamentous
Microfilament
Microfilaments are the thinnest filaments of the cytoskeleton, a structure found in the cytoplasm of all eukaryotic cells. These linear polymers of actin subunits are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton...
actin (F-actin) with the fourth of its cortactin repeats. As the concentration of phosphorylated cortactin increases in specific regions within the cell, the monomers each begin to recruit an Arp2/3 complex to F-actin. It binds to Arp2/3 with an aspartic acid-aspartic acid-tryptophan (DDW) sequence in its NTA region, a motif that is often seen in other actin nucleation-promoting factors (NPFs).
Certain serine/threonine kinases, such as ERK
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
, can phosphorylate cortactin on Ser405 and Ser418 in the SH3 domain. Activated like this, it still associates with Arp2/3 and F-actin, but will also allow other actin NPFs, most importantly N-WASp (Neuronal Wiskott-Aldrich syndrome protein
Wiskott-Aldrich syndrome protein
The Wiskott–Aldrich Syndrome Protein is a 502-amino acid protein that is expressed in cells of the hematopoietic system. In the inactive state, WASp exists in an auto-inhibited conformation with sequences near its C-terminus binding to a region near its N-terminus...
), to bind to the complex as well; when phosphorylated by tyrosine kinases, other NPFs are excluded. The ability of these other NPFs to bind the Arp2/3 complex while cortactin is also bound could come from new interactions with cortactin’s SH3 domain, which is in a different conformation when phosphorylated by Ser/Thr kinases and thus may be more open to interactions with other NPFs. Having other NPFs bind to the Arp2/3 complex at the same time as cortactin may enhance nucleation site stability.
Location and function in the cell
Inactive cortactin is diffuse throughout the cytoplasm, but upon phosphorylation, the protein begins to target certain areas in the cell. Cortactin-assisted Arp2/3-nucleated actin branches are most prominent in the actin cortex, around the periphery of the cell. A phosphorylated cortactin monomer binds to, activates, and stabilizes an Arp2/3 complex on preexisting F-actin, which provides a nucleation site for a new actin branch to form from the “mother” filament. Branches formed from cortactin-assisted nucleation sites are very stable; cortactin has been shown to inhibit debranching. Thus, polymerization and branching of actin is promoted in areas of the cell where cortactin is localized.Cortactin is very active in lamellipodia, protrusions of the cell membrane formed by actin polymerization and treadmilling
Treadmilling
Treadmilling is a phenomenon observed in many cellular cytoskeletal filaments, especially in actin filaments and microtubules. It occurs when one end of a filament grows in length while the other end shrinks resulting in a section of filament seemingly "moving" across a stratum or the cytosol...
that propel the cell along a surface as it migrates towards some target.
Cortactin acts as a link between extracellular signals and lamellipodial “steering.” When a receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
on the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
binds to an adhesion site, for example, cortactin will be phosphorylated locally to the area of binding, activate and recruit Arp2/3 to the actin cortex in that region, and thus stimulate cortical actin polymerization and movement of the cell in that direction. Macrophages, highly mobile immune cells that engulf cellular debris and pathogens, are propelled by lamellipodia and identify/migrate toward a target via chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
; thus, cortactin must also be activated by receptor kinases that pick up a large variety of chemical signals.
Studies have implicated cortactin in both clathrin
Clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
-mediated endocytosis and clathrin-independent endocytosis. In both kinds of endocytosis, it has long been known that actin localizes to sites of vesicle invagination and is a vital part of the endocytic pathway, but the actual mechanisms by which actin facilitates endocytosis are still unclear. Recently, however, it has been found that dynamin
Dynamin
Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamins are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with, another compartment, both at the cell surface as well as at the...
, the protein responsible for breaking the newly formed vesicular bud off the inside of the plasma membrane, can associate with the SH3 domain of cortactin. Since cortactin recruits the Arp2/3 complexes that lead to actin polymerization, this suggests that it may play an important part in linking vesicle formation to the as yet unknown functions actin has in endocytosis.
Clinical significance
Amplification of the genes encoding cortactin—in humans, EMS1—has been found to occur in certain tumors. Overexpression of cortactin can lead to highly-active lamellipodia in tumor cells, dubbed “invadopodia.” These cells are especially invasive and migratory, making them very dangerous, for they can easily spread cancer across the body into other tissues.Interactions
Cortactin has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with WIPF1
WIPF1
WAS/WASL-interacting protein family member 1 is a protein that in humans is encoded by the WIPF1 gene.-Interactions:WIPF1 has been shown to interact with Wiskott-Aldrich syndrome protein, Cortactin and NCK1.-Further reading:...
, KCNA2
KCNA2
Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the KCNA2 gene.-Interactions:KCNA2 has been shown to interact with KCNA4, DLG4, PTPRA, KCNAB2, RHOA and Cortactin....
, FER
FER (gene)
Proto-oncogene tyrosine-protein kinase FER is an enzyme that in humans is encoded by the FER gene.-Interactions:FER has been shown to interact with TMF1 and Cortactin.-Further reading:...
, CTNND1
CTNND1
Catenin delta-1 is a protein that in humans is encoded by the CTNND1 gene.-Interactions:CTNND1 has been shown to interact with Beta-catenin, FYN, Collagen, type XVII, alpha 1, PTPN6, YES1, PTPRJ, VE-cadherin, MUC1, CDH1, CDH2, PTPRM, Cortactin, Nephrin, ZBTB33 and PSEN1.-Further reading:...
, SHANK2
SHANK2
SH3 and multiple ankyrin repeat domains protein 2 is a protein that in humans is encoded by the SHANK2 gene. Two alternative splice variants, encoding distinct isoforms, are reported...
, ARPC2
ARPC2
Actin-related protein 2/3 complex subunit 2 is a protein that in humans is encoded by the ARPC2 gene.-Interactions:ARPC2 has been shown to interact with Cortactin.-Further reading:...
, ACTR3
ACTR3
Actin-related protein 3 is a protein that in humans is encoded by the ACTR3 gene.-Interactions:ACTR3 has been shown to interact with Cortactin.-Further reading:...
and WASL
WASL (gene)
Neural Wiskott-Aldrich syndrome protein is a protein that in humans is encoded by the WASL gene.The Wiskott-Aldrich syndrome family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton...
.