PHIP drives glioblastoma motility and invasion by regulating the focal adhesion complex.

Autor:	de Semir D; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Bezrookove V; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Nosrati M; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Scanlon KR; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Singer E; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Judkins J; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Rieken C; Carl Zeiss Microscopy, LLC, New York, NY 10594., Wu C; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Shen J; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Schmudermayer C; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Dar AA; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Miller JR 3rd; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Cobbs C; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Yount G; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Desprez PY; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Debs RJ; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Salomonis N; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229., McAllister S; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Cleaver JE; Department of Dermatology and Pharmaceutical Chemistry, University of California, San Francisco, CA 94121 james.cleaver@ucsf.edu kashani@cpmcri.org., Soroceanu L; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107., Kashani-Sabet M; California Pacific Medical Center (CPMC) Research Institute, San Francisco, CA 94107; james.cleaver@ucsf.edu kashani@cpmcri.org.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Apr 21; Vol. 117 (16), pp. 9064-9073. Date of Electronic Publication: 2020 Apr 09.
DOI:	10.1073/pnas.1914505117
Abstrakt:	The invasive behavior of glioblastoma is essential to its aggressive potential. Here, we show that pleckstrin homology domain interacting protein (PHIP), acting through effects on the force transduction layer of the focal adhesion complex, drives glioblastoma motility and invasion. Immunofluorescence analysis localized PHIP to the leading edge of glioblastoma cells, together with several focal adhesion proteins: vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), as well as phosphorylated forms of paxillin (pPXN) and focal adhesion kinase (pFAK). Confocal microscopy specifically localized PHIP to the force transduction layer, together with TLN1 and VCL. Immunoprecipitation revealed a physical interaction between PHIP and VCL. Targeted suppression of PHIP resulted in significant down-regulation of these focal adhesion proteins, along with zyxin (ZYX), and produced profoundly disorganized stress fibers. Live-cell imaging of glioblastoma cells overexpressing a ZYX-GFP construct demonstrated a role for PHIP in regulating focal adhesion dynamics. PHIP silencing significantly suppressed the migratory and invasive capacity of glioblastoma cells, partially restored following TLN1 or ZYX cDNA overexpression. PHIP knockdown produced substantial suppression of tumor growth upon intracranial implantation, as well as significantly reduced microvessel density and secreted VEGF levels. PHIP copy number was elevated in the classical glioblastoma subtype and correlated with elevated EGFR levels. These results demonstrate PHIP's role in regulating the actin cytoskeleton, focal adhesion dynamics, and tumor cell motility, and identify PHIP as a key driver of glioblastoma migration and invasion. Competing Interests: Competing interest statement: C.C. and J.D.L. are coauthors on a 2018 research article.
Databáze:	MEDLINE
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