MAP4K4 regulates integrin-FERM binding to control endothelial cell motility

Philip Vitorino, Stacey Yeung, Ailey Crow, Jesse Bakke, Tanya Smyczek, Kristina West, Erin McNamara, Jeffrey Eastham-Anderson, Stephen Gould, Seth F. Harris, Chudi Ndubaku, Weilan Ye

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-Π21-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to Π21-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, α 5Π21-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.

Original languageEnglish
Pages (from-to)425-430
Number of pages6
Issue number7544
StatePublished - Mar 26 2015


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