BMP2K phosphorylates AP‐2 and regulates clathrin‐mediated endocytosis

• Published in: Traffic (Copenhagen, Denmark) Denmark), 2021-11, Vol.22 (11), p.377-396
• Main Authors: Ramesh, Shikha T., Navyasree, Kolaparamba V., Sah, Sneha, Ashok, Anjitha B., Qathoon, Nishada, Mohanty, Suryasikha, Swain, Rajeeb K., Umasankar, Perunthottathu K.
• Format: Article
• Language: English
• Subjects: Adaptor Protein Complex 2 - metabolism; adaptor protein complex AP‐2; Animals; BMP2K; Clathrin; Clathrin - metabolism; clathrin‐mediated endocytosis; Embryos; Endocytosis; Endocytosis - physiology; Gastrulation; Internalization; Localization; Phenotypes; Phosphorylation; Zebrafish - metabolism
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12814

Phosphorylation of the central adaptor protein complex, AP‐2 is pivotal for clathrin‐mediated endocytosis (CME). Here, we uncover the role of an uncharacterized kinase (BMP‐2 inducible kinase—BMP2K) in AP‐2 phosphorylation. We demonstrate that BMP2K can phosphorylate AP‐2 in vitro and in vivo. Functional impairment of BMP2K impedes AP‐2 phosphorylation leading to defects in clathrin‐coated pit (CCP) morphology and cargo internalization. BMP2K engages AP‐2 via its extended C‐terminus and this interaction is important for its CCP localization and function. Notably, endogenous BMP2K levels decline upon functional impairment of AP‐2 indicating AP‐2 dependent BMP2K stabilization in cells. Further, functional inactivation of BMP2K in zebrafish embryos yields gastrulation phenotypes which mirror AP‐2 loss‐of‐function suggesting physiological relevance of BMP2K in vertebrates. Together, our findings propose involvement of a novel kinase in AP‐2 phosphorylation and in the operation of CME. AP‐2 is a heterotetrameric adaptor protein complex central to clathrin‐mediated endocytosis (CME). Muniscin family of proteins (muniscins) activates AP‐2 from a closed, inactive state in the cytosol to an open membrane bound state which facilitates clathrin and cargo binding. Here we show that AP‐2 and muniscins likely co‐ordinate the recruitment and stabilization of a previously uncharacterized kinase, BMP2K in clathrin‐coated pits (CCPs). This results in phosphorylation of AP‐2 leading to efficient clathrin‐mediated endocytosis.