<p>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.</p>