Abstract
Cytokines comprise a large family of secreted ligands that are critical for the regulation of immune homeostasis. Cytokines initiate signaling via dimerization or oligomerization of the cognate receptor subunits, triggering the activation of the Janus Kinases (JAKs)/ signal transducer and activator of transcription (STATs) pathway and the induction of specific gene expression programs and bioactivities. Deregulation of cytokines or their downstream signaling pathways are at the root of many human disorders including autoimmunity and cancer. Identifying and understanding the mechanistic principles that govern cytokine signaling will, therefore, be highly important in order to harness the therapeutic potential of cytokines. In this review, we will analyze how biophysical (ligand-receptor binding geometry and affinity) and cellular (receptor trafficking and intracellular abundance of signaling molecules) parameters shape the cytokine signalosome and cytokine functional pleiotropy; from the initial cytokine binding to its receptor to the degradation of the cytokine receptor complex in the proteasome and/or lysosome. We will also discuss how combining advanced protein engineering with detailed signaling and functional studies has opened promising avenues to tackle complex questions in the cytokine signaling field.
| Original language | English |
|---|---|
| Article number | 2143 |
| Number of pages | 9 |
| Journal | Frontiers in Immunology |
| Volume | 9 |
| DOIs | |
| Publication status | Published - 27 Sep 2018 |
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Keywords
- JAK/STAT signaling pathway
- cytokine signaling
- endosomal trafficking
- endosomes signaling
- protein engineering
Cite this
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Mapping determinants of cytokine signaling via protein engineering. / Gorby, Claire; Martinez-Fabregas, Jonathan; Wilmes, Stephan; Moraga Gonzalez, Ignacio (Lead / Corresponding author).
In: Frontiers in Immunology, Vol. 9, 2143, 27.09.2018.Research output: Contribution to journal › Review article
TY - JOUR
T1 - Mapping determinants of cytokine signaling via protein engineering
AU - Gorby, Claire
AU - Martinez-Fabregas, Jonathan
AU - Wilmes, Stephan
AU - Moraga Gonzalez, Ignacio
PY - 2018/9/27
Y1 - 2018/9/27
N2 - Cytokines comprise a large family of secreted ligands that are critical for the regulation of immune homeostasis. Cytokines initiate signaling via dimerization or oligomerization of the cognate receptor subunits, triggering the activation of the Janus Kinases (JAKs)/ signal transducer and activator of transcription (STATs) pathway and the induction of specific gene expression programs and bioactivities. Deregulation of cytokines or their downstream signaling pathways are at the root of many human disorders including autoimmunity and cancer. Identifying and understanding the mechanistic principles that govern cytokine signaling will, therefore, be highly important in order to harness the therapeutic potential of cytokines. In this review, we will analyze how biophysical (ligand-receptor binding geometry and affinity) and cellular (receptor trafficking and intracellular abundance of signaling molecules) parameters shape the cytokine signalosome and cytokine functional pleiotropy; from the initial cytokine binding to its receptor to the degradation of the cytokine receptor complex in the proteasome and/or lysosome. We will also discuss how combining advanced protein engineering with detailed signaling and functional studies has opened promising avenues to tackle complex questions in the cytokine signaling field.
AB - Cytokines comprise a large family of secreted ligands that are critical for the regulation of immune homeostasis. Cytokines initiate signaling via dimerization or oligomerization of the cognate receptor subunits, triggering the activation of the Janus Kinases (JAKs)/ signal transducer and activator of transcription (STATs) pathway and the induction of specific gene expression programs and bioactivities. Deregulation of cytokines or their downstream signaling pathways are at the root of many human disorders including autoimmunity and cancer. Identifying and understanding the mechanistic principles that govern cytokine signaling will, therefore, be highly important in order to harness the therapeutic potential of cytokines. In this review, we will analyze how biophysical (ligand-receptor binding geometry and affinity) and cellular (receptor trafficking and intracellular abundance of signaling molecules) parameters shape the cytokine signalosome and cytokine functional pleiotropy; from the initial cytokine binding to its receptor to the degradation of the cytokine receptor complex in the proteasome and/or lysosome. We will also discuss how combining advanced protein engineering with detailed signaling and functional studies has opened promising avenues to tackle complex questions in the cytokine signaling field.
KW - JAK/STAT signaling pathway
KW - cytokine signaling
KW - endosomal trafficking
KW - endosomes signaling
KW - protein engineering
UR - http://www.scopus.com/inward/record.url?scp=85054893654&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2018.02143
DO - 10.3389/fimmu.2018.02143
M3 - Review article
C2 - 30319612
VL - 9
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 2143
ER -