Highlights d Persister BRAF-mutant melanoma cells emerge during RAF and MEK inhibition d Persister cells escape cell-cycle arrest via sporadic receptordriven ERK pulses d ERK pulses arise spontaneously in neighboring cells via autocrine/paracrine signaling d Oncogenic vs. receptor-driven MAPK signaling are differentially sensitive to inhibitors
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.
Cytokine and growth factor receptors are activated when the soluble growth factor binds and alters the protein‐protein interactions between receptor components on the cell surface, triggering intracellular receptor phosphorylation and downstream signaling. However, many receptors involve three or more cell surface components, and the effect of this additional complexity on how ligand binding is quantitatively coupled to receptor activation and signaling is not well understood. The RET receptor tyrosine kinase is an example of such a multi‐component receptor. RET is activated when the binding of a growth factor such as artemin (ART) brings about assembly of a pentameric complex that includes two copies of RET plus two copies of the GPI‐linked co‐receptor, GFRα3. We show here that RET can be directly activated by agonist antibodies, bypassing its GFRα co‐receptors. The signaling profiles of two agonist antibodies differ from each other, and from the natural ligand ART, in the level of downstream signal amplification. This result suggests that the activated receptor complexes that are formed by these different agonists engage with downstream signaling pathways in distinct ways, presumably reflecting different geometries within each complex, and thus show that activated RET can exist in multiple forms with different signaling properties. We also show that we can achieve higher signal amplitudes and a biological response similar to that seen with ART by using the agonist antibodies, but only if we cluster the activated receptor complexes using either monoclonal or polyclonal secondary anti‐Fc antibodies. This finding suggests that, while RET dimerization represents a minimum requirement for activation, higher‐order clustering might be required for a full biological response.
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