Membrane lipids and cell signaling

Abstract

Purpose of review: Reception and transmission of signals across the plasma membrane has been a function generally attributed to transmembrane proteins. In the last 3 years, however, a growing number of reports have further acknowledged important contributions played by membrane lipids in the process of signal transduction.

Recent findings: In particular, the constituency of membrane lipids can regulate how proteins with SH2 domains and molecules like K-Ras expose their catalytic domains to the cytosol and interact with effectors and second messengers. Recent reports have also shown that the degree of saturation of phospholipids can reduce the activation of certain G-protein-coupled receptors, and signaling downstream to Toll-like receptor 4 with consequences to nuclear factor kappa B activation and inflammation. Levels of specific gangliosides in the membrane were reported to activate integrins in a cell-autonomous manner affecting tumor cell migration. Furthermore, high resolution of the association of cholesterol with the smoothened receptor has clarified its participation in sonic hedgehog signaling. These are some of the key advancements that have further propelled our understanding of the broad versatile contributions of membrane lipids in signal transduction.

Summary: As we gain definitive detail regarding the impact of lipid-protein interactions and their consequences to cell function, the options for therapeutic targeting expand with the possibility of greater specificity.

Figure 1. Impact of lipid membrane composition on signaling responses

(a) Side view shows relative orientations (O1-5) of K-RAS4A influenced by anionic membrane composition. Top view illustrates a view of K-RAS4A from its rotational axis, showing which GTPase residues are in closest proximity to the membrane at the various orientations. Darkness of the bilayer indicates more prevalent orientations. (b) SH2 domain modulation of receptor tyrosine kinase signal transduction based membrane lipid binding affinity. In the absence of such affinity, SH2 domains have transient signaling in comparison to those with ACPs. Specific binding pockets in addition to ACPs confer higher affinity and sustain binding/prolong signal transduction. (c) Signaling through α5β1 integrin promotes cytoskeletal remodeling and migration through interactions with GM2. The mechanism of interaction involves direct binding of GM2 with the integrin receptor in either cis or trans configurations. (d) Sterol-dependent signal transduction of Hh mediated de-repression of Smo. Subcellular location of sterol incorporation has yet to be established, though molecular bobbing induced by excess free membrane cholesterol could provide the impetus for association. (e) Reduction of TLR4 mediated inflammatory signaling through decreased membrane lipid packing facilitated by membrane enrichment of PUFAs and LXR/ABCA1 mediated cholesterol efflux. Abbreviations (not found in text): focal adhesion kinase (FAK), Sarcoma proto-oncogene tyrosine-protein kinase (Src), Patched (Ptc), Toll-like receptor 4 (TLR4), retinoid X receptor (RXR).