A Thousand and One Receptor Tyrosine Kinases

Abstract

Over twenty years ago, a series of seminal studies in PC12 neurons provided a framework for how receptor tyrosine kinases generate many different outcomes despite activating a set of shared intracellular pathways. In this essay, we revisit the question of receptor tyrosine kinase specificity. We first examine the relationship between receptor phosphorylation and intracellular pathway activation. We then consider the mechanisms through which signaling dynamics encode distinct cellular outcomes and finally discuss how two different receptors drive divergent transcriptional responses within the same developmental context. Establishing the key parameters that dictate the response to growth factor stimulation is critical for determining how receptor tyrosine kinases orchestrate development, an essential prerequisite for understanding the pathological consequences when such signaling processes go awry.

Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2

“…While Spry2/4 and Etv4/5 are detected in all ICM cells, Dusp4 expression correlates with PrE (Figure 6B and S6). These downstream targets can regulate the MAPK/ERK cascade via positive and negative feedback to produce specific context-dependent responses (Brewer et al, 2016; Buday et al, 1995; Ekerot et al, 2008; Kholodenko, 2006; Shindo et al, 2016; Vasudevan and Soriano, 2016). Therefore, the association of EPI- and PrE-biased cells with distinct targets indicates that differential levels of FGF signaling in lineage-biased cells may be augmented by distinct feedback (Figure 6A).…”

“…Thus we envisage a model whereby the differential signaling activity in lineage-biased ICM cells elicited by the different sets of FGF targets and receptors associated with them results in divergent responses within each lineage-biased cell – upregulation of Gata6 and the PrE program, or downregulation of Gata6 and maturation of the EPI, from a common signal, FGF4 (Ferrell and Machleder, 1998; Lemmon and Schlessinger, 2010; Lesokhin et al, 1999; Mackeigan et al, 2005; Vasudevan and Soriano, 2016; Yang and Baker, 2003). While mechanisms for the transcriptional regulation of distinct FGF targets and receptors in EPI- and PrE-biased cells are still unclear, we speculate that the initial heterogeneity among ICM cells at the time of TE versus ICM specification (E2.5 16- to 32-cell stage) would precede and might permit the heterogeneous expression of different targets in individual cells (Burton et al, 2013).…”

FGF/FGFR signaling in health and disease

“…In addition, it is appreciated that mutations of individual FGFs or FGFRs can have detrimental effects, but a systematic understanding of intracellular pathway activation and dynamics is still lacking. 750 To mimic the effects obtained from omics and conditional knockout study, we need to use targeted therapy approaches, which means to precisely modulate individual FGFs, FGFRs, and downstream signaling in specific types of cells at specific disease stages. The good news is that we are having more and more approach to exert these targeted treatments.…”

A threshold model for receptor tyrosine kinase signaling specificity and cell fate determination

“…For instance, the Ras/MAPK and PI3K/Akt signaling pathways share cAMP response element-binding protein (CREB), estrogen receptors, and GATA2 as transcription factors 25 – 28 . Accordingly, how RTKs elicit their distinct cellular/developmental responses through the use of a shared set of intracellular pathways constitutes a puzzle that has preoccupied researchers in the field for at least two decades 29 .…”