Filamin A phosphorylation at S2152: A molecular switch fueling cancer and neurodegeneration

Best known for crosslinking actin to form the cytoskeleton, the scaffolding protein filamin A (FLNA) is an unusually complex intracellular regulator, interacting with a vast array of receptors, cytoskeletal proteins and signaling molecules to expand its regulatory function from structural dynamics to focal adhesion, cell migration and diverse cell signaling. This review focuses on the interplay between FLNA’s conformation, its phosphorylation at S2152 and changes in its protein interactions that alter its function and contribute to cancer, metastasis, Alzheimer’s and potentially other age-related diseases. Various cellular stressors can induce these conformational and phosphorylation changes. Normally quiescent, FLNA has an auto-inhibitory loop that can be unfurled by mechanical or other stress or by phosphorylation at S2152, and reciprocally, S2152 phosphorylation is induced upon dismantling the auto-inhibitory conformation, in an amplifying process. S2152 phosphorylated FLNA contributes to integrin activation, leading to cell adhesion and migration, and supports non-canonical roles of elements of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, impeding ER calcium replenishment and sustaining UPR, leading to either proliferation and migration or cell death, depending on cell type. In cancer cells, S2152 phosphorylated FLNA enhances activation of cancer signaling molecules K-RAS and mechanistic target of rapamycin (mTOR), while impairing anti-proliferative signaling at other receptors. In Alzheimer’s disease, S2152 phosphorylated FLNA enables sustained inflammatory signaling and pathogenic signaling that hyperphosphorylates tau. Because S2152 phosphorylation of FLNA contributes to integrin activation, cell adhesion, proliferation, metastasis, inflammation and neurodegeneration, agents that reduce this phosphorylation may have broad therapeutic utility. Known as a scaffolding protein, filamin A is a large protein inside cells that helps crosslink the small protein actin to provide structural and mobility support to cells. Filamin A also interacts with a large number of other proteins, including receptors spanning the cell membrane and signaling proteins inside cells, serving as a regulator for a wide variety of cell processes. This review focuses on a particular modification that adds a phosphate group onto the 2152nd amino acid in the filamin A protein. This phosphorylation affects filamin A’s shape, its interacting protein partners, its behavior, and ultimately, the health or disease fate of the cell. When this specific phosphorylation persists, it can amplify the stress on a cell and cause the cell to migrate and multiply as a survival strategy, or to degenerate and die if the cell is unable to divide. For this reason, this phosphorylation is a common event in both cancer and in neurodegeneration, as seen in Alzheimer’s disease. Additionally, this phosphorylation can promote certain cell signaling pathways that drive cancer and impede signaling pathways that are protective against cancer. Finally, this specific phosphorylation of filamin A enables toxic signaling in neurons and fuels inflammation in Alzheimer’s disease brains. Because this filamin A phosphorylation elicits multiple pathological processes in cancer, Alzheimer’s disease and potentially other age-related diseases, agents that reverse or reduce this modification may be useful to treat these diseases.