MAP4K4 controlled integrin β1 activation and c-Met endocytosis are associated with invasive behavior of medulloblastoma cells
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Dimitra Tripolitsioti1, Karthiga Santhana Kumar1, Anuja Neve1, Jessica Migliavacca1, Charles Capdeville1, Elisabeth J. Rushing2, Min Ma1, Noriyuki Kijima3, Ashish Sharma4, Martin Pruschy4, Scott McComb1, Michael D. Taylor3, Michael A. Grotzer1,5 and Martin Baumgartner1
1University Children’s Hospital Zürich, Department of Oncology, Children’s Research Center, Zürich, Switzerland
2Institute of Neuropathology, University Hospital Zürich, Zürich, Switzerland
3Division of Neurosurgery, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
4Department of Radiation Oncology, University Hospital Zürich, Zürich, Switzerland
5University Children’s Hospital Zürich, Department of Oncology, Zürich, Switzerland
Martin Baumgartner, email: [email protected]
Keywords: medulloblastoma; MAP4K4; integrin β1; c-Met; cell migration and invasion
Received: November 16, 2017 Accepted: April 08, 2018 Published: May 01, 2018
Local tissue infiltration of Medulloblastoma (MB) tumor cells precedes metastatic disease but little is still known about intrinsic regulation of migration and invasion in these cells.
We found that MAP4K4, a pro-migratory Ser/Thr kinase, is overexpressed in 30% of primary MB tumors and that increased expression is particularly associated with the frequently metastatic SHH β subtype. MAP4K4 is a driver of migration and invasion downstream of c-Met, which is transcriptionally up-regulated in SHH MB. Consistently, depletion of MAP4K4 in MB tumor cells restricts HGF-driven matrix invasion in vitro and brain tissue infiltration ex vivo. We show that these pro-migratory functions of MAP4K4 involve the activation of the integrin β-1 adhesion receptor and are associated with increased endocytic uptake. The consequent enhanced recycling of c-Met caused by MAP4K4 results in the accumulation of activated c-Met in cytosolic vesicles, which is required for sustained signaling and downstream pathway activation.
The parallel increase of c-Met and MAP4K4 expression in SHH MB could predict an increased potential of these tumors to infiltrate brain tissue and cause metastatic disease. Molecular targeting of the underlying accelerated endocytosis and receptor recycling could represent a novel approach to block pro-migratory effector functions of MAP4K4 in metastatic cancers.
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