Publication Date:
2015-03-25
Description:
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-beta1-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 beta1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, alpha5beta1-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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vitorino, Philip -- Yeung, Stacey -- Crow, Ailey -- Bakke, Jesse -- Smyczek, Tanya -- West, Kristina -- McNamara, Erin -- Eastham-Anderson, Jeffrey -- Gould, Stephen -- Harris, Seth F -- Ndubaku, Chudi -- Ye, Weilan -- England -- Nature. 2015 Mar 26;519(7544):425-30. doi: 10.1038/nature14323. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Chemical Biology and Therapeutics Department, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Translational Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Pathology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Structural Biology Department, Genentech, Inc., South San Francisco, California 94080, USA. ; Discovery Chemistry Department, Genentech, Inc., South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799996" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Motifs
;
Animals
;
Antigens, CD29/chemistry/drug effects/metabolism
;
Cell Membrane/drug effects/metabolism
;
*Cell Movement
;
Cell Shape/drug effects
;
Endothelial Cells/*cytology/drug effects/*metabolism
;
Epistasis, Genetic
;
Focal Adhesions/metabolism
;
Humans
;
Integrin alpha1/drug effects/metabolism
;
Integrins/drug effects/*metabolism
;
Intracellular Signaling Peptides and Proteins/antagonists &
;
inhibitors/deficiency/genetics/*metabolism
;
Male
;
Mice
;
Microfilament Proteins/deficiency/genetics/metabolism
;
Neovascularization, Pathologic
;
Phosphorylation
;
Protein Binding
;
Protein Structure, Tertiary
;
Protein-Serine-Threonine Kinases/antagonists &
;
inhibitors/deficiency/genetics/*metabolism
;
Talin/chemistry/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
