Ankrd26 is a retinoic acid-responsive plasma membrane-binding and -shaping protein critical for proper cell differentiation

Morphogens are important triggers for differentiation processes. Yet, downstream effectors that organize cell shape changes in response to morphogenic cues, such as retinoic acid, largely remain elusive. Additionally, derailed plasma membrane-derived signaling often is associated with cancer. We identify Ankrd26 as a critical player in cellular differentiation and as plasma membrane-localized protein able to self-associate and form clusters at the plasma membrane in response to retinoic acid. We show that Ankrd26 uses an N-terminal amphipathic structure for membrane binding and bending. Importantly, in an acute myeloid leukemia-associated Ankrd26 mutant, this critical structure was absent, and Ankrd26's membrane association and shaping abilities were impaired. In line with this, the mutation rendered Ankrd26 inactive in both gain-of-function and loss-of-function/rescue studies addressing retinoic acid/brain-derived neurotrophic factor (BDNF)-induced neuroblastoma differentiation. Our results highlight the importance and molecular details of Ankrd26-mediated organizational platforms for cellular differentiation at the plasma membrane and how impairment of these platforms leads to cancer-associated pathomechanisms involving these Ankrd26 properties.