Syntrophins were first identified in the postsynaptic membranes of the Torpedo electric organ. Alpha-1-syntrophin is a 58 kDa peripheral cytoplasmic membrane adaptor protein and is a member of the syntrophin family. It is encoded by the SNTA gene in humans and is 505 amino acids long. The full-length cDNA is 2,163 bp long. It encodes a single large open reading frame which maps to chromosome 20q11.2 (Adams et al. 1993, 1995; Ahn et al. 1994; Yang et al. 1994). The human alpha-1-syntrophin is 94% identical to the mouse sequence and about 93% identical to the rabbit sequence (Ahn et al. 1994, 1996a). Alpha-1-syntrophin is the acidic isoform (pI = 6.7) of the syntrophin family. It was the first isoform of the syntrophin to be discovered (Adams et al. 1995; Froehner et al. 1997) and has since been cloned and characterized (Ahn et al. 1996a). Alpha-1-syntrophin exists as a monomer as well as a dimer in the cell. Alpha-1-syntrophin is expressed in skeletal muscles (Ahn et al. 1996a) and mammalian tissues like heart, brain, stomach, breasts, etc. It forms a part of the dystrophin glycoprotein complex (DGC) in muscle cells or is concentrated at the neuromuscular junction in the brain.
Alpha-1-Syntrophin and Cell Signaling
The split PH1 domain and the SU domain are involved in interactions between alpha-1-syntrophin and the DGC. These domains allow alpha-1-syntrophins to interact with several proteins, glycoproteins, lipids, receptors, etc., and to play a key role in linking several cell components to the DGC and, therefore, regulate many downstream signaling pathways.
Alpha-1-syntrophin also binds stress-activated protein kinase 3 (SAPK3) (Hasegawa et al. 1999). This binding occurs via the KETXL sequence on the C-terminal of the PDZ domain. SAPK3 phosphorylates alpha-1-syntrophin on serine-193 and serine-201 residues. In skeletal muscle cells, Neuronal nitric oxide synthase (nNOS) has been shown to bind to alpha-1-syntrophin, localizing it to the sarcolemma via the DGC. The sarcolemmal calcium pump, nNOS and alpha-1-syntrophin form a ternary complex with each other. The PDZ domain of nNOS binds to the PDZ domain of alpha-1-syntrophin. Grb2 binds to alpha-1-syntrophin via its SH2 domain when alpha-1-syntrophin is phosphorylated on a tyrosine residue. This binding of Grb2 to the phosphorylated alpha-1-syntrophin allows Grb2 to activate Son of Sevenless (Sos1) protein. The activated Sos1 protein in turn activates Rac1 protein and the rest of the signaling pathway. Unphosphorylated alpha-1-syntrophin binds to the C-terminal SH3 domain of Grb2 (Madhavan et al. 1992; Oak et al. 2001, 2003; Bhat et al. 2014). The signaling pathway via the DGC links the matrix laminin binding on the outside of the sarcolemma to the DGC on the inside. This signaling pathway has been described as alpha-1-syntrophin-Grb2-Sos1-Rac1-PAK1-JNK followed by the phosphorylation of c-jun on S65 and the rest of the pathway. The binding of laminin induces a conformational change in alpha-1-syntrophin, which in turn leads to its phosphorylation of a tyrosine residue. This phosphorylation is crucial for its binding to Grb2 and activation of Sos1 and Rac1.
Alpha-1-Syntrophin and the Cytoskeleton
Through its association with the DGC, alpha-1-syntrophin has been shown to act as the link between the extracellular matrix, the internal cell signaling apparatus, and the actin cytoskeleton (Adams et al. 2000).
It has been seen that actin depolymerization leads to a reduction in the tyrosine phosphorylation of alpha-1-syntrophin as well as a reduction in the interaction between alpha-1-syntrophin and Rac1 protein in breast carcinoma cells. This actin depolymerization mediated loss of tyrosine phosphorylation of alpha-1-syntrophin further leads to a loss of Rac1 activation and an increase in cell apoptosis, a decrease in cell migration, and a decrease in intracellular ROS production in breast carcinoma cells (Bhat et al. 2016).
Alpha-1-syntrophin is a membrane associated protein of the syntrophin family. The domain organization of alpha-1-syntrophin is PH1, PDZ, PH2, and SU domains. It is via these domains that alpha-1-syntrophin functions as an adaptor protein and binds various signaling molecules. Alpha-1-syntrophin is expressed in skeletal muscles and mammalian tissues like heart, brain, stomach, breasts, etc. It forms a part of the dystrophin glycoprotein complex (DGC) in muscle cells and via the DGC forms a part of cell signaling pathways. Alpha-1-syntrophin has been shown to be involved in cytoskeleton organization via its interaction with TAPP1 protein. It also binds actin via PH2 and SU domain. Alpha-1-syntrophin also plays a role in the regulation of ROS generation, Rac1 activation, cell proliferation, apoptosis, and cell migration. By mediating these processes, alpha-1-syntrophin is fast emerging as a regulator of carcinogenesis and can possibly be used as a therapeutic target aimed at preventing pathologies like cancer in the future.