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 and Weilan Ye ()
Additional contact information
Philip Vitorino: Genentech, Inc., South San Francisco, California 94080, USA
Stacey Yeung: Genentech, Inc., South San Francisco, California 94080, USA
Ailey Crow: Genentech, Inc., South San Francisco, California 94080, USA
Jesse Bakke: St Jude Children’s Research Hospital
Tanya Smyczek: Genentech, Inc., South San Francisco, California 94080, USA
Kristina West: Genentech, Inc., South San Francisco, California 94080, USA
Erin McNamara: Genentech, Inc., South San Francisco, California 94080, USA
Jeffrey Eastham-Anderson: Genentech, Inc., South San Francisco, California 94080, USA
Stephen Gould: Genentech, Inc., South San Francisco, California 94080, USA
Seth F. Harris: Genentech, Inc., South San Francisco, California 94080, USA
Chudi Ndubaku: Genentech, Inc., South San Francisco, California 94080, USA
Weilan Ye: Genentech, Inc., South San Francisco, California 94080, USA

Nature, 2015, vol. 519, issue 7544, 425-430

Abstract: Abstract 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–β1-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 β1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, α5β1-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.

Date: 2015
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DOI: 10.1038/nature14323

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