Multifarious Determinants of Cytokine Receptor Signaling Specificity

Moraga, Ignacio; Spangler, Jamie B.; Mendoza, Juan L.; García, K. Christopher

doi:10.1016/b978-0-12-800100-4.00001-5

Cited by 59 publications

(57 citation statements)

References 192 publications

(264 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since GFs and cytokines act on multiple different cell types that express their receptors, they tend to exhibit pleiotropic activities, which has limited their clinical utility as agonists (Moraga et al, 2014; Nicola, 1994; Thomas et al, 2004; Yea et al, 2015). Pleiotropic actions can induce counterbalancing cellular activities, resulting in blunted therapeutic efficacy (Hart et al, 2014; Lin et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

Chhabra

Starkl

et al. 2017

Cell

Self Cite

View full text Add to dashboard Cite

SUMMARY Most secreted growth factors and cytokines are functionally pleiotropic because their receptors are expressed on diverse cell types. While important for normal mammalian physiology, pleiotropy limits the efficacy of cytokines and growth factors as therapeutics. Stem cell factor (SCF) is a growth factor that acts through the c-Kit receptor tyrosine kinase to elicit hematopoietic progenitor expansion, but can be toxic when administered in vivo because it concurrently activates mast cells. We engineered a mechanism-based SCF partial agonist that impaired c-Kit dimerization, truncating downstream signaling amplitude. This SCF variant elicited biased activation of hematopoietic progenitors over mast cells in vitro and in vivo. Mouse models of SCF-mediated anaphylaxis, radioprotection, and hematopoietic expansion revealed that this SCF partial agonist retained therapeutic efficacy while exhibiting virtually no anaphylactic off-target effects. The approach of biasing cell activation by tuning signaling thresholds and outputs has applications to many dimeric receptor-ligand systems.

show abstract

Section: Introductionmentioning

confidence: 99%

Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

Chhabra

Starkl

et al. 2017

Cell

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cells lacking one of the receptors lack normal IFN signaling (4,5). Structurally different members of type I IFNs bind to the same cell surface receptor but mediate differential responses that result from differences in binding affinities, concentration of IFN, and duration of activation (5)(6)(7)(8)(9)(10)(11)(12)(13). Differential signaling is realized through robust (antiviral) versus tunable (antiproliferative and immunomodulatory) gene induction leading to different phenotypic outcomes (14,15).…”

mentioning

confidence: 99%

“…Receptor dimerization drives the activation of cytosolic associated Janus family kinases (JAKs), which in turn initiate downstream signaling cascades that propagate the signal into the nucleus and regulate gene transcription mainly via signal transducer and activator of transcription (STAT) proteins (11, 13, 16 -18). Detailed information exists on the structure function relations of the extracellular domains (5, 7), although less is known on the intracellular domains (9,(11)(12)(13).…”

mentioning

confidence: 99%

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Sharma

Longjam

Schreiber

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Type I interferons serve as the first line of defense against pathogen invasion. Binding of IFNs to its receptors, IFNAR1 and IFNAR2, is leading to activation of the IFN response. To determine whether structural perturbations observed during binding are propagated to the cytoplasmic domain, multiple mutations were introduced into the transmembrane helix and its surroundings. Insertion of one to five alanine residues near either the N or C terminus of the transmembrane domain (TMD) likely promotes a rotation of 100°and a translation of 1.5 Å per added residue. Surprisingly, the added alanines had little effect on the binding affinity of IFN to the cell surface receptors, STAT phosphorylation, or gene induction. Similarly, substitution of the juxtamembrane residues of the TMD with alanines, or replacement of the TMD of IFNAR1 with that of IFNAR2, did not affect IFN binding or activity. Finally, only the addition of 10 serine residues (but not 2 or 4) between the extracellular domain of IFNAR1 and the TMD had some effect on signaling. Bioinformatic analysis shows a correlation between high sequence conservation of TMDs of cytokine receptors and the ability to transmit structural signals. Sequence conservation near the TMD of IFNAR1 is low, suggesting limited functional importance for this region. Our results suggest that IFN binding to the extracellular domains of IFNAR1 and IFNAR2 promotes proximity between the intracellular domains and that differential signaling is a function of duration of activation and affinity of binding rather than specific conformational changes transmitted from the outside to the inside of the cell.Type I interferons (IFNs) orchestrate the antiviral innate immunity in vertebrates. They consist of 16 members in humans as follows: 12 different IFN␣ subtypes, as well as IFN␤, IFN, IFN⑀, and IFN. They are clustered on the short arm of chromosome 9. All type I interferons elicit their innate and adaptive immune responses after binding to the receptor and forming the IFNAR1-IFN-IFNAR2 ternary complex (1, 2), the formation of which is essential for signaling. Both IFNAR1 and IFNAR2 belong to the class II helical cytokine receptors with four fibronectin type III-like subdomains for IFNAR1 and two subdomains for IFNAR2. The extracellular domains are followed by a single helix of 21 amino acids spanning the membrane, which in turn is connected to mostly natively unstructured intracellular domains and their associated effectors (Fig. 1A) (3). Cells lacking one of the receptors lack normal IFN signaling (4, 5). Structurally different members of type I IFNs bind to the same cell surface receptor but mediate differential responses that result from differences in binding affinities, concentration of IFN, and duration of activation (5-13). Differential signaling is realized through robust (antiviral) versus tunable (antiproliferative and immunomodulatory) gene induction leading to different phenotypic outcomes (14,15). Receptor dimerization drives the activation of cytosolic associated Janus family kina...

show abstract

“…High combinatorial plasticity of these pathways allows them to respond to many different ligands on the one hand, but on the other leads to a high degree of cross talk between different ligands (3,(7)(8)(9). A striking example is signaling of the Type I Interferon family in which 16 different Interferon subtypes bind to the same heterodimeric receptor but elicit distinct cellular responses (10,11).…”

Section: Dimeric Receptors Often Participate In Overlapping Signalingmentioning

confidence: 99%

“…How cells can reliably discriminate between different signals in such conditions remains a puzzle (3,7,9,13).…”

Section: Mathematical Description Of Receptor Bindingmentioning

confidence: 99%

Absolute Ligand Discrimination by Dimeric Signaling Receptors

Fathi

Nayak

Feld

et al. 2016

Biophysical Journal

View full text Add to dashboard Cite

Many signaling pathways act through shared components, where different ligand molecules bind the same receptors or activate overlapping sets of response regulators downstream. Nevertheless, different ligands acting through cross-wired pathways often lead to different outcomes in terms of the target cell behavior and function. Although a number of mechanisms have been proposed, it still largely remains unclear how cells can reliably discriminate different molecular ligands under such circumstances. Here we show that signaling via ligand-induced receptor dimerization-a very common motif in cellular signaling-naturally incorporates a mechanism for the discrimination of ligands acting through the same receptor.

show abstract

Multifarious Determinants of Cytokine Receptor Signaling Specificity

Cited by 59 publications

References 192 publications

Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Absolute Ligand Discrimination by Dimeric Signaling Receptors

Contact Info

Product

Resources

About