Syntrophin proteins as Santa Claus: role(s) in cell signal transduction

Abstract

Syntrophins are a family of cytoplasmic membrane-associated adaptor proteins, characterized by the presence of a unique domain organization comprised of a C-terminal syntrophin unique (SU) domain and an N-terminal pleckstrin homology (PH) domain that is split by insertion of a PDZ domain. Syntrophins have been recognized as an important component of many signaling events, and they seem to function more like the cell's own personal 'Santa Claus' that serves to 'gift' various signaling complexes with precise proteins that they 'wish for', and at the same time care enough for the spatial, temporal control of these signaling events, maintaining overall smooth functioning and general happiness of the cell. Syntrophins not only associate various ion channels and signaling proteins to the dystrophin-associated protein complex (DAPC), via a direct interaction with dystrophin protein but also serve as a link between the extracellular matrix and the intracellular downstream targets and cell cytoskeleton by interacting with F-actin. They play an important role in regulating the postsynaptic signal transduction, sarcolemmal localization of nNOS, EphA4 signaling at the neuromuscular junction, and G-protein mediated signaling. In our previous work, we reported a differential expression pattern of alpha-1-syntrophin (SNTA1) protein in esophageal and breast carcinomas. Implicated in several other pathologies, like cardiac dys-functioning, muscular dystrophies, diabetes, etc., these proteins provide a lot of scope for further studies. The present review focuses on the role of syntrophins in membrane targeting and regulation of cellular proteins, while highlighting their relevance in possible development and/or progression of pathologies including cancer which we have recently demonstrated.

Fig. 1

Schematic representation of the various members of syntrophin family proteins and their general distribution in mammalian tissues

Fig. 2

Common structural organization of the syntrophin proteins

Fig. 3

Diagrammatic representation of the various interactions shown within the cell

Fig. 4

Regulation of cytoskeleton organization by syntrophins

Fig. 5

Role of syntrophins in the membrane localization of ionic channel

Fig. 6

Schematic representation of the many roles of syntrophin proteins in cell signaling

Fig. 7

Diagrammatic representation of the multi-complex formation between PMCA, α-1-syntrophin, NOS, and the SCNA5 sodium channel. PMCA via its intracellular loop, located between trans-membrane domains 4 and 5, binds to the linker region of syntrophin, and via its COOH terminus binds to the PDZ domain of NOS-1. Syntrophin also connects the SCN5A sodium channel to the nNOS–PMCA complex and regulates NO concentration at the membrane