The breast cancer susceptibility gene product (γ-synuclein) alters cell behavior through it interaction with phospholipase Cβ

Abstract

The breast cancer susceptibility gene protein, also known as γ-synuclein, is highly expressed in human breast cancer in a stage-specific manner, with highest expression in late stage cancer. In model systems, γ-synuclein binds phospholipase Cβ2 which is regulated by Gαq to generate intracellular Ca2+ signals. PLCβ2, which is also absent in normal tissue but highly expressed in breast cancer, is additionally regulated by Rac to promote migration pathways. We have found that γ-synuclein binds to the same region of PLCβ2 as Gαq. Using cells that mimic stage 4 breast cancer (MDA MB 231), we show that down-regulation of γ-synuclein reduces the protein level of PLCβ but increases the transcript level over 40 fold. γ-Synuclein down-regulation also promotes the interaction between Gαq and PLCβ resulting in a stronger Ca2+ response to Gαq agonists. The ability of γ-synuclein to interfere with Gαq-PLCβ interactions allows more PLCβ to colocalize with Rac impacting Rac-mediated pathways that may give rise to cancerous phenotypes.

Synuclein gamma expression enhances radiation resistance of breast cancer cells

“…It is hypothesized that SNCG affects the mRNA levels of several regulatory proteins but in ways that are difficult to predict [ 48 ]. Thus, SNCG binds and mediates AP-1 activity [ 49 , 50 ], activates Jun Kinase 1 (JNK1) [ 12 ], activates Estrogen Receptor (ER-α) transcription [ 22 ], interacts with androgen receptor (AR) [ 30 ], with HER2 [ 42 ], with AKT [ 34 ], with phospholipase Cβ2 [ 48 ], with PolyC binding protein 1 (PCBP1) [ 51 ]. The molecular mechanisms of how SNCG favors radioresistance remain to be determined and further research is required to unveil those mechanisms.…”

Phospholipase Cβ3 Membrane Adsorption and Activation Are Regulated by Its C-Terminal Domains and Phosphatidylinositol 4,5-Bisphosphate

“…Finally, the CTDs have emerged as protein interaction sites. The proximal CTD interacts with the RNA silencing complex C3PO , and synucleins, − whereas the distal CTD is reported to interact with numerous proteins, including the M3 muscarinic receptor, the translin-associated factor-X, and scaffolding proteins. − These protein–protein interactions are likely to perturb intramolecular interactions within PLCβ, in addition to its interactions with Gα q and the cell membrane. These PLCβ binding partners may impose an additional level of regulation on the membrane association of PLCβ, alone or in complex with its G protein activators, its subcellular distribution, and its lipase activity.…”