Dataset Information

MAP4K4 controlled integrin ?1 activation and c-Met endocytosis are associated with invasive behavior of medulloblastoma cells.

ABSTRACT: 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 ? 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 ?-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.

SUBMITTER: Tripolitsioti D

PROVIDER: S-EPMC5955425 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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MAP4K4 controlled integrin β1 activation and c-Met endocytosis are associated with invasive behavior of medulloblastoma cells.

Tripolitsioti Dimitra D Kumar Karthiga Santhana KS Neve Anuja A Migliavacca Jessica J Capdeville Charles C Rushing Elisabeth J EJ Ma Min M Kijima Noriyuki N Sharma Ashish A Pruschy Martin M McComb Scott S Taylor Michael D MD Grotzer Michael A MA Baumgartner Martin M

Oncotarget 20180501 33

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 ...[more]

PMID: 29796184

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Project description:The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/?1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/?1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/?1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and ?1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/?1 complex to maintain the high-affinity ?1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/?1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced ?5 integrin from ?1 integrin, creating a complex with much greater affinity for fibronectin (FN) than ?5?1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/?1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.

Dataset Information

MAP4K4 controlled integrin ?1 activation and c-Met endocytosis are associated with invasive behavior of medulloblastoma cells.

Publications

MAP4K4 controlled integrin β1 activation and c-Met endocytosis are associated with invasive behavior of medulloblastoma cells.

Similar Datasets

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