PT  - JOURNAL ARTICLE
AU  - Shikha T. Ramesh
AU  - Kolaparamba V. Navyasree
AU  - Anjitha B. Ashok
AU  - Nishada Qathoon
AU  - Suryasikha Mohanty
AU  - Rajeeb K. Swain
AU  - Perunthottathu K. Umasankar
TI  - Allosteric feed-forward activation of AP-2 <em>via</em> FCHO-BMP2K axis promotes clathrin-mediated endocytosis
AID  - 10.1101/870899
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 870899
4099  - http://biorxiv.org/content/early/2019/12/10/870899.short
4100  - http://biorxiv.org/content/early/2019/12/10/870899.full
AB  - Spatio-temporal regulation of central adaptor complex, AP-2 is pivotal for clathrin-mediated endocytosis (CME). We recently discovered that FCHO proteins trigger clathrin-coated pit (CCP) formation by allosterically activating AP-2 on plasma membrane (Umasankar et al., 2014). Here, we demonstrate that this activation promotes AP-2 phosphorylation via recruitment and stabilization of BMP-2 inducible kinase (BMP2K), a bona fide AP-2 kinase leading to CCP maturation. Accordingly, BMP2K mislocalizes and degrades in FCHO knockout/ AP-2 depleted cells. Functional inactivation of kinase impairs AP-2 phosphorylation leading to altered lattice morphology and CME phenotypes reminiscent of CCP maturation defects. Reexpression of FCHO rescues AP-2 phosphorylation defects in FCHO knockout cells implying membrane activation of AP-2 is a prerequisite for kinase function. Furthermore, gain- and loss-of function phenotypes of FCHO and BMP2K are analogous and mirror altered AP-2 functions during zebrafish embryogenesis. Together, our findings reveal an in vivo allosteric feed-forward axis for operation of CME.