Understanding cytokine and growth factor receptor activation mechanisms

Abstract

Our understanding of the detailed mechanism of action of cytokine and growth factor receptors – and particularly our quantitative understanding of the link between structure, mechanism and function – lags significantly behind our knowledge of comparable functional protein classes such as enzymes, G protein-coupled receptors, and ion channels. In particular, it remains controversial whether such receptors are activated by a mechanism of ligand-induced oligomerization, versus a mechanism in which the ligand binds to a pre-associated receptor dimer or oligomer that becomes activated through subsequent conformational rearrangement. A major limitation to progress has been the relative paucity of methods for performing quantitative mechanistic experiments on unmodified receptors expressed at endogenous levels on live cells. In this article we review the current state of knowledge on the activation mechanisms of cytokine and growth factor receptors, critically evaluate the evidence for and against the different proposed mechanisms, and highlight other key questions that remain unanswered. New approaches and techniques have led to rapid recent progress in this area, and the field is poised for major advances in the coming years, which promises to revolutionize our understanding of this large and biologically and medically important class of receptors.

IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization

“…Increased efficiency made possible by better stability, amplification of their affinity or the protective mechanisms of the proteins are amongst the main benefits of this oligomerization process. By forming homodimers, M-CSFR, M-CSF and IL-34, like numerous other cytokines/receptors, do not break this oligomerization rule [35]. To increase the complexity, diversity and regulation of cell signaling events, several cytokines are able to form heteromeric structures.…”

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

“…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).…”

RNA-antimicrobial peptide LL-37 complexes fuel a TLR- and NET-mediated inflammatory cycle of neutrophil activation in psoriasis

“…helper, CD3 + CD8 + cytotoxic T cells and CD14 + HLA-DR + monocytes, whereas higher concentrations had a weaker effect, i.e. showed a bell-shaped dose response curve not uncommon for cytokines 32 . Due to donor-to-donor variation observed throughout in the human system, only a non-significant, moderate effect of MIP-1β was observed (Fig.…”