Disentangling biological signaling networks by dynamic coupling of signaling lipids to modifying enzymes

Abstract

An unresolved problem in biological signal transduction is how particular branches of highly interconnected signaling networks can be decoupled, allowing activation of specific circuits within complex signaling architectures. Although signaling dynamics and spatiotemporal mechanisms serve critical roles, it remains unclear if these are the only ways cells achieve specificity within networks. The transcription factor Steroidogenic Factor-1 (SF-1) is an excellent model to address this question, as it forms dynamic complexes with several chemically distinct lipid species (phosphatidylinositols, phosphatidylcholines and sphingolipids). This property is important since lipids bound to SF-1 are modified by lipid signaling enzymes (IPMK & PTEN), regulating SF-1 biological activity in gene expression. Thus, a particular SF-1/lipid complex can interface with a lipid signaling enzyme only if SF-1 has been loaded with a chemically compatible lipid substrate. This mechanism permits dynamic downstream responsiveness to constant upstream input, disentangling specific pathways from the full network. The potential of this paradigm to apply generally to nuclear lipid signaling is discussed, with particular attention given to the nuclear receptor superfamily of transcription factors and their phospholipid ligands.

The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1

“…5C). The inositol lipid kinase IPMK, previously shown to phosphorylate PIP 2 bound to SF-1, can also be docked onto the SF-1/PIP 2 structure without significant steric interference (32). The functional significance of the opposing or "flipped" orientations of the PIP 2 and PIP 3 head groups in the SF-1 LBD structures presented here remains unclear.…”

Phosphoinositide-specific phospholipase C in health and disease

“…3 ). IP3 acts as a substrate for inositol polyphosphate multikinase (IPMK), which is located in the nucleus and gives rise to higher inositol phosphates ( 24 ).…”

Phospholipid regulation of the nuclear receptor superfamily

“…In fact, many members of the nuclear receptor superfamily have been identified as being translated on membrane-bound ribosomes (Reid and Nicchitta, 2015). One hypothesis explaining this phenomenon is that membrane-translated proteins are co-translationally sensing the ER lipid content by acquiring lipids from the ER as the proteins fold in close proximity to this membrane system (Blind, 2014). PLTPs such as Sec14 (Figure 3C) and TIPE3 (Figure 3) are localized to ER membranes, and could facilitate this process through the same poorly understood mechanisms they use to assist in the movement of phospholipids into lipoprotein particles in the cytoplasm.…”

“…This discovery represents a new way that small signaling molecules can alter receptor function - small molecules statically associated with an effector can be metabolized/altered while bound to the protein, altering effector function. We posit that the direct modification of second messenger small signaling molecules bound to intracellular receptors will prove to be a general signaling paradigm, particularly in the regulation of nuclear protein/small molecule complexes (Blind, 2014). Importantly, this mechanism is capable of decoupling second messenger-bound downstream effectors from the activation of particular upstream signaling pathways.…”

“…When the cell requires SF-1 to be sensitive to ceramide metabolism, sphingosine occupies the SF-1 ligand-binding pocket. If the cell wants to decouple SF-1 activity from phosphoinositide and ceramide metabolism, PC may occupy the ligand-binding pocket (Blind, 2014). It is not difficult to see the advantage that decoupling an effector from particular signaling pathways, while sensitizing it to others, may confer to complex nuclear signaling systems.…”