Location, location, location: PDE4D5 function is directed by its unique N-terminal region

Abstract

Compartmentalised cAMP SignallingCharacterisation of the cyclic AMP signalling pathway in glycogenolysis as the first "second messenger" system opened the door for study of "cellular signalling" as a Depending on receptor type, cAMP produced at the cell membrane can reach far into the cell or stay localised to its site of production. The distance cAMP travels and its ability to form three-dimensional gradients, triggering activation of cAMP effectors, are determined by the phosphodiesterase (PDE) landscape [8]. Often, PDEs are expressed at low levels yet it is their localisation to demarcated positions within cells that underpins both their effectiveness and function. Indeed, reporter technology devised to visualise cAMP gradient formation following specific receptor activation [9] has confirmed that PDE positioning is crucial to the formation of multiple, simultaneous and spatially distinct cAMP gradients that drive defined physiological responses. PDE familiesPDEs are a vast super-family of distinct, highly regulated enzymes which can be classified based on primary structure into class I, II and III -the largest, class I,

Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system

“…Among others, this period is characterized by a distinct reduction of PKAc levels attributed to reduced ribosome translation or stability of the kinase subunit 17,18 . Activation of phosphodiesterases (PDE) counteracts cAMP levels and control the duration and amplitude of downstream signaling 19,20 . The binding of the endogenous protein kinase inhibitor (PKI) to PKAc also contributes to the attenuation of cAMP signaling in hormone-stimulated cells 21,22 .…”

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…For instance, PDE4D5 is involved in a number of processes common in almost all cells, such as cell growth, cell orientation, desensitization of Gs-coupled receptors, and inactivating the phosphorylation of ubiquitous chaperone HSP20 (263). The ability for PDE4D5 to have all these functions in a cell is a result of it being localized in different compartments by different anchors (e.g., RACK1 at leading edge of cells, beta-arrestin at transmembrane receptors, and HSP20 in the cytosol;…”

Phosphodiesterase Type 4 anchoring regulates cAMP signaling to Popeye domain-containing proteins

“…4B). This situation has similarities to the association of PDE4D5 with beta-arrestin-2 where all PDE4s can interact with the scaffold but PDE4D5 is "preferred" due to an optimized binding motif within the PDE's Nterminal region (Wills et al, 2016).…”

“…A good example that illustrates the concept is the PDE type 4 isoform called PDE4D5 (Wills et al, 2016). It can be translocated to the vicinity of G s -coupled receptors by the signaling scaffold protein beta-arrestin in order to hydrolyze cAMP, while beta-arrestin concomitantly hinders G-protein signaling (Baillie et al, 2003).…”