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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

Fyn is capable of activating divergent signaling cascades. (A) In the active conformation, the SH2 and SH3 domains bind downstream effectors and activate divergent signaling cascades in lymphocytes. The interaction between PI(3)K-p85α and the SH3 domain of Fyn controls multiple aspects of lymphocyte effector functions. The SH2 domain of Fyn binds ADAP via the YDGI motif following tyrosine phosphorylation by Fyn. This stabilizes ADAP and initiates a unique set of lymphocyte functions, such as cytokine production. (B) ADAP translocation and stabilization leads to CBM complex formation. Carma1 binds to ADAP and initiates the recruitment of Bcl10 and Malt1. This leads to TAK1 binding and activation of its kinase activity. TAK1 then activates NF-κB or AP-1. Once activated, NF-κB and AP1 translocate to the nucleus where they induce transcription of cytokine and chemokine genes.
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Figure 3: Fyn is capable of activating divergent signaling cascades. (A) In the active conformation, the SH2 and SH3 domains bind downstream effectors and activate divergent signaling cascades in lymphocytes. The interaction between PI(3)K-p85α and the SH3 domain of Fyn controls multiple aspects of lymphocyte effector functions. The SH2 domain of Fyn binds ADAP via the YDGI motif following tyrosine phosphorylation by Fyn. This stabilizes ADAP and initiates a unique set of lymphocyte functions, such as cytokine production. (B) ADAP translocation and stabilization leads to CBM complex formation. Carma1 binds to ADAP and initiates the recruitment of Bcl10 and Malt1. This leads to TAK1 binding and activation of its kinase activity. TAK1 then activates NF-κB or AP-1. Once activated, NF-κB and AP1 translocate to the nucleus where they induce transcription of cytokine and chemokine genes.

Mentions: The SH3 domain of Fyn is able to bind the PI(3)K-p85α subunit and, through phosphorylation, initiate PI(3)K activity (Figure 3). Structural data show that a Pro-rich region corresponding to residues 91–104 of PI(3)K-p85α is able to adopt a helical conformation and bind the SH3 domain of Fyn (19). This binding leads to phosphorylation and activation of PI(3)K-p85α (49). These interactions occur downstream of receptor-mediated activation and are critical for lymphocyte effector function (50–52). Studies with PI(3)K-p85α-deficient murine NK cells show loss of cytokine production and anti-tumor cytotoxicity (53). In addition to these functional defects, loss of PI(3)K-p85α also impairs lineage commitment and terminal maturation (53). These data demonstrate the ability of Fyn to activate multiple lymphocyte effector functions through activation of PI(3)K signaling.


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

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

Fyn is capable of activating divergent signaling cascades. (A) In the active conformation, the SH2 and SH3 domains bind downstream effectors and activate divergent signaling cascades in lymphocytes. The interaction between PI(3)K-p85α and the SH3 domain of Fyn controls multiple aspects of lymphocyte effector functions. The SH2 domain of Fyn binds ADAP via the YDGI motif following tyrosine phosphorylation by Fyn. This stabilizes ADAP and initiates a unique set of lymphocyte functions, such as cytokine production. (B) ADAP translocation and stabilization leads to CBM complex formation. Carma1 binds to ADAP and initiates the recruitment of Bcl10 and Malt1. This leads to TAK1 binding and activation of its kinase activity. TAK1 then activates NF-κB or AP-1. Once activated, NF-κB and AP1 translocate to the nucleus where they induce transcription of cytokine and chemokine genes.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Fyn is capable of activating divergent signaling cascades. (A) In the active conformation, the SH2 and SH3 domains bind downstream effectors and activate divergent signaling cascades in lymphocytes. The interaction between PI(3)K-p85α and the SH3 domain of Fyn controls multiple aspects of lymphocyte effector functions. The SH2 domain of Fyn binds ADAP via the YDGI motif following tyrosine phosphorylation by Fyn. This stabilizes ADAP and initiates a unique set of lymphocyte functions, such as cytokine production. (B) ADAP translocation and stabilization leads to CBM complex formation. Carma1 binds to ADAP and initiates the recruitment of Bcl10 and Malt1. This leads to TAK1 binding and activation of its kinase activity. TAK1 then activates NF-κB or AP-1. Once activated, NF-κB and AP1 translocate to the nucleus where they induce transcription of cytokine and chemokine genes.
Mentions: The SH3 domain of Fyn is able to bind the PI(3)K-p85α subunit and, through phosphorylation, initiate PI(3)K activity (Figure 3). Structural data show that a Pro-rich region corresponding to residues 91–104 of PI(3)K-p85α is able to adopt a helical conformation and bind the SH3 domain of Fyn (19). This binding leads to phosphorylation and activation of PI(3)K-p85α (49). These interactions occur downstream of receptor-mediated activation and are critical for lymphocyte effector function (50–52). Studies with PI(3)K-p85α-deficient murine NK cells show loss of cytokine production and anti-tumor cytotoxicity (53). In addition to these functional defects, loss of PI(3)K-p85α also impairs lineage commitment and terminal maturation (53). These data demonstrate the ability of Fyn to activate multiple lymphocyte effector functions through activation of PI(3)K signaling.

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