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

doi:10.1038/nature14323

MAP4K4 regulates integrin-FERM binding to control endothelial cell motility

Nature. 2015 Mar 26;519(7544):425-30. doi: 10.1038/nature14323. Epub 2015 Mar 18.

Authors

Affiliations

¹ Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA.
² Chemical Biology and Therapeutics Department, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
³ Translational Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA.
⁴ Pathology Department, Genentech, Inc., South San Francisco, California 94080, USA.
⁵ Structural Biology Department, Genentech, Inc., South San Francisco, California 94080, USA.
⁶ Discovery Chemistry Department, Genentech, Inc., South San Francisco, California 94080, USA.

PMID: 25799996
DOI: 10.1038/nature14323

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.

MeSH terms

Amino Acid Motifs
Animals
Cell Membrane / drug effects
Cell Membrane / metabolism
Cell Movement*
Cell Shape / drug effects
Endothelial Cells / cytology*
Endothelial Cells / drug effects
Endothelial Cells / metabolism*
Epistasis, Genetic
Focal Adhesions / metabolism
Humans
Integrin alpha1 / drug effects
Integrin alpha1 / metabolism
Integrin beta1 / chemistry
Integrin beta1 / drug effects
Integrin beta1 / metabolism
Integrins / drug effects
Integrins / metabolism*
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / deficiency
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Male
Mice
Microfilament Proteins / deficiency
Microfilament Proteins / genetics
Microfilament Proteins / metabolism
Neovascularization, Pathologic
Phosphorylation
Protein Binding
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Protein Structure, Tertiary
Talin / chemistry
Talin / metabolism

Substances

Integrin alpha1
Integrin beta1
Integrins
Intracellular Signaling Peptides and Proteins
Microfilament Proteins
Talin
moesin
MAP4K4 protein, human
Protein Serine-Threonine Kinases