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The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells.

Gerbec ZJ, Thakar MS, Malarkannan S - Front Immunol (2015)

Bottom Line: Specifically, the Fyn signaling axis represents a branch point for killer cell effector functions and provides a model for how cytotoxicity and cytokine production are differentially regulated.While the Fyn-PI(3)K pathway controls multiple functions, including cytotoxicity, cell development, and cytokine production, the Fyn-ADAP pathway preferentially regulates cytokine production in NK and T cells.In this review, we discuss how the structure of Fyn controls its function in lymphocytes and the role this plays in mediating two facets of lymphocyte effector function, cytotoxicity and production of inflammatory cytokines.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Medical College of Wisconsin , Milwaukee, WI , USA ; Department of Microbiology, Immunology and Molecular Genetics, Medical College of Wisconsin , Milwaukee, WI , USA.

ABSTRACT
Lymphocyte signaling cascades responsible for anti-tumor cytotoxicity and inflammatory cytokine production must be tightly regulated in order to control an immune response. Disruption of these cascades can cause immune suppression as seen in a tumor microenvironment, and loss of signaling integrity can lead to autoimmunity and other forms of host-tissue damage. Therefore, understanding the distinct signaling events that exclusively control specific effector functions of "killer" lymphocytes (T and NK cells) is critical for understanding disease progression and formulating successful immunotherapy. Elucidation of divergent signaling pathways involved in receptor-mediated activation has provided insights into the independent regulation of cytotoxicity and cytokine production in lymphocytes. Specifically, the Fyn signaling axis represents a branch point for killer cell effector functions and provides a model for how cytotoxicity and cytokine production are differentially regulated. While the Fyn-PI(3)K pathway controls multiple functions, including cytotoxicity, cell development, and cytokine production, the Fyn-ADAP pathway preferentially regulates cytokine production in NK and T cells. In this review, we discuss how the structure of Fyn controls its function in lymphocytes and the role this plays in mediating two facets of lymphocyte effector function, cytotoxicity and production of inflammatory cytokines. This offers a model for using mechanistic and structural approaches to understand clinically relevant lymphocyte signaling.

No MeSH data available.


Related in: MedlinePlus

Models for inhibition and activation of Fyn. (A) Fyn regulation is reliant on phosphorylation of an inhibitory tyrosine, Tyr531, in the C-terminal regulatory region. This is initiated by binding of the SH3 domain of open Fyn to PAG/CBP (gray) (left). This leads to subsequent phosphorylation of tyrosine residues on PAG/CBP, and these tyrosine residues bind the SH2 domains of both Fyn and Csk (pink) (center). Csk then phosphorylates the C-terminal inhibitory Tyr531, which leads to intramolecular binding of the Fyn SH2 domain and disrupts the interaction of Fyn with PAG/CBP. Fyn is then released from PAG/CBP and remains anchored in the membrane as an inactive kinase molecule (right). (B) Fyn is locked in the inactive conformation until cellular activation leads to disruption of intramolecular binding. Stimulation through NKG2D leads to activation of the CD45 phosphatase (left). CD45 then removes the phosphate from the C-terminal inhibitory tyrosine and disrupts the intramolecular interactions responsible for keeping Fyn in a closed conformation. These interactions are also disrupted upon binding of substrates, such as PI(3)K-p85α, to the Fyn SH3 domain. This prevents the SH3 domain from binding to the linker region. Loss of these intramolecular interactions causes Fyn to adopt a more open conformation where the SH2 and SH3 domains are able to mediate substrate recruitment, while the kinase domain mediates enzymatic activity (right).
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Figure 2: Models for inhibition and activation of Fyn. (A) Fyn regulation is reliant on phosphorylation of an inhibitory tyrosine, Tyr531, in the C-terminal regulatory region. This is initiated by binding of the SH3 domain of open Fyn to PAG/CBP (gray) (left). This leads to subsequent phosphorylation of tyrosine residues on PAG/CBP, and these tyrosine residues bind the SH2 domains of both Fyn and Csk (pink) (center). Csk then phosphorylates the C-terminal inhibitory Tyr531, which leads to intramolecular binding of the Fyn SH2 domain and disrupts the interaction of Fyn with PAG/CBP. Fyn is then released from PAG/CBP and remains anchored in the membrane as an inactive kinase molecule (right). (B) Fyn is locked in the inactive conformation until cellular activation leads to disruption of intramolecular binding. Stimulation through NKG2D leads to activation of the CD45 phosphatase (left). CD45 then removes the phosphate from the C-terminal inhibitory tyrosine and disrupts the intramolecular interactions responsible for keeping Fyn in a closed conformation. These interactions are also disrupted upon binding of substrates, such as PI(3)K-p85α, to the Fyn SH3 domain. This prevents the SH3 domain from binding to the linker region. Loss of these intramolecular interactions causes Fyn to adopt a more open conformation where the SH2 and SH3 domains are able to mediate substrate recruitment, while the kinase domain mediates enzymatic activity (right).

Mentions: The quaternary structure of Fyn also provides extrinsic regulation that helps maintain Fyn in an inactive state as evidenced by studies in multiple cell types. When Fyn is co-translationally myristoylated, the carbon chain of the myristoyl group causes translocation of the protein to the plasma membrane (17). Once at the membrane, interaction of Fyn with an adaptor protein and regulatory kinase forces Fyn into a closed conformation (Figure 2A). These events are driven by processive phosphorylation, wherein all available sites of a given substrate are phosphorylated before the kinase dissociates.


The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells.

Gerbec ZJ, Thakar MS, Malarkannan S - Front Immunol (2015)

Models for inhibition and activation of Fyn. (A) Fyn regulation is reliant on phosphorylation of an inhibitory tyrosine, Tyr531, in the C-terminal regulatory region. This is initiated by binding of the SH3 domain of open Fyn to PAG/CBP (gray) (left). This leads to subsequent phosphorylation of tyrosine residues on PAG/CBP, and these tyrosine residues bind the SH2 domains of both Fyn and Csk (pink) (center). Csk then phosphorylates the C-terminal inhibitory Tyr531, which leads to intramolecular binding of the Fyn SH2 domain and disrupts the interaction of Fyn with PAG/CBP. Fyn is then released from PAG/CBP and remains anchored in the membrane as an inactive kinase molecule (right). (B) Fyn is locked in the inactive conformation until cellular activation leads to disruption of intramolecular binding. Stimulation through NKG2D leads to activation of the CD45 phosphatase (left). CD45 then removes the phosphate from the C-terminal inhibitory tyrosine and disrupts the intramolecular interactions responsible for keeping Fyn in a closed conformation. These interactions are also disrupted upon binding of substrates, such as PI(3)K-p85α, to the Fyn SH3 domain. This prevents the SH3 domain from binding to the linker region. Loss of these intramolecular interactions causes Fyn to adopt a more open conformation where the SH2 and SH3 domains are able to mediate substrate recruitment, while the kinase domain mediates enzymatic activity (right).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4584950&req=5

Figure 2: Models for inhibition and activation of Fyn. (A) Fyn regulation is reliant on phosphorylation of an inhibitory tyrosine, Tyr531, in the C-terminal regulatory region. This is initiated by binding of the SH3 domain of open Fyn to PAG/CBP (gray) (left). This leads to subsequent phosphorylation of tyrosine residues on PAG/CBP, and these tyrosine residues bind the SH2 domains of both Fyn and Csk (pink) (center). Csk then phosphorylates the C-terminal inhibitory Tyr531, which leads to intramolecular binding of the Fyn SH2 domain and disrupts the interaction of Fyn with PAG/CBP. Fyn is then released from PAG/CBP and remains anchored in the membrane as an inactive kinase molecule (right). (B) Fyn is locked in the inactive conformation until cellular activation leads to disruption of intramolecular binding. Stimulation through NKG2D leads to activation of the CD45 phosphatase (left). CD45 then removes the phosphate from the C-terminal inhibitory tyrosine and disrupts the intramolecular interactions responsible for keeping Fyn in a closed conformation. These interactions are also disrupted upon binding of substrates, such as PI(3)K-p85α, to the Fyn SH3 domain. This prevents the SH3 domain from binding to the linker region. Loss of these intramolecular interactions causes Fyn to adopt a more open conformation where the SH2 and SH3 domains are able to mediate substrate recruitment, while the kinase domain mediates enzymatic activity (right).
Mentions: The quaternary structure of Fyn also provides extrinsic regulation that helps maintain Fyn in an inactive state as evidenced by studies in multiple cell types. When Fyn is co-translationally myristoylated, the carbon chain of the myristoyl group causes translocation of the protein to the plasma membrane (17). Once at the membrane, interaction of Fyn with an adaptor protein and regulatory kinase forces Fyn into a closed conformation (Figure 2A). These events are driven by processive phosphorylation, wherein all available sites of a given substrate are phosphorylated before the kinase dissociates.

Bottom Line: Specifically, the Fyn signaling axis represents a branch point for killer cell effector functions and provides a model for how cytotoxicity and cytokine production are differentially regulated.While the Fyn-PI(3)K pathway controls multiple functions, including cytotoxicity, cell development, and cytokine production, the Fyn-ADAP pathway preferentially regulates cytokine production in NK and T cells.In this review, we discuss how the structure of Fyn controls its function in lymphocytes and the role this plays in mediating two facets of lymphocyte effector function, cytotoxicity and production of inflammatory cytokines.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Medical College of Wisconsin , Milwaukee, WI , USA ; Department of Microbiology, Immunology and Molecular Genetics, Medical College of Wisconsin , Milwaukee, WI , USA.

ABSTRACT
Lymphocyte signaling cascades responsible for anti-tumor cytotoxicity and inflammatory cytokine production must be tightly regulated in order to control an immune response. Disruption of these cascades can cause immune suppression as seen in a tumor microenvironment, and loss of signaling integrity can lead to autoimmunity and other forms of host-tissue damage. Therefore, understanding the distinct signaling events that exclusively control specific effector functions of "killer" lymphocytes (T and NK cells) is critical for understanding disease progression and formulating successful immunotherapy. Elucidation of divergent signaling pathways involved in receptor-mediated activation has provided insights into the independent regulation of cytotoxicity and cytokine production in lymphocytes. Specifically, the Fyn signaling axis represents a branch point for killer cell effector functions and provides a model for how cytotoxicity and cytokine production are differentially regulated. While the Fyn-PI(3)K pathway controls multiple functions, including cytotoxicity, cell development, and cytokine production, the Fyn-ADAP pathway preferentially regulates cytokine production in NK and T cells. In this review, we discuss how the structure of Fyn controls its function in lymphocytes and the role this plays in mediating two facets of lymphocyte effector function, cytotoxicity and production of inflammatory cytokines. This offers a model for using mechanistic and structural approaches to understand clinically relevant lymphocyte signaling.

No MeSH data available.


Related in: MedlinePlus