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  1. Article ; Online: Abl Kinases Regulate HGF/Met Signaling Required for Epithelial Cell Scattering, Tubulogenesis and Motility.

    Ran Li / Jennifer F Knight / Morag Park / Ann Marie Pendergast

    PLoS ONE, Vol 10, Iss 5, p e

    2015  Volume 0124960

    Abstract: Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth ...

    Abstract Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth factor (HGF) and is dysregulated in numerous human tumors. Here we show that Abl family of non-receptor tyrosine kinases, comprised of Abl (ABL1) and Arg (ABL2), are activated downstream of the Met receptor, and that inhibition of Abl kinases dramatically suppresses HGF-induced cell scattering and tubulogenesis. We uncover a critical role for Abl kinases in the regulation of HGF/Met-dependent RhoA activation and RhoA-mediated actomyosin contractility and actin cytoskeleton remodeling in epithelial cells. Moreover, treatment of breast cancer cells with Abl inhibitors markedly decreases Met-driven cell migration and invasion. Notably, expression of a transforming mutant of the Met receptor in the mouse mammary epithelium results in hyper-activation of both Abl and Arg kinases. Together these data demonstrate that Abl kinases link Met activation to Rho signaling and Abl kinases are required for Met-dependent cell scattering, tubulogenesis, migration, and invasion. Thus, inhibition of Abl kinases might be exploited for the treatment of cancers driven by hyperactivation of HGF/Met signaling.
    Keywords Medicine ; R ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer

    Jennifer F. Knight / Vanessa Y.C. Sung / Elena Kuzmin / Amber L. Couzens / Danielle A. de Verteuil / Colin D.H. Ratcliffe / Paula P. Coelho / Radia M. Johnson / Payman Samavarchi-Tehrani / Tina Gruosso / Harvey W. Smith / Wontae Lee / Sadiq M. Saleh / Dongmei Zuo / Hong Zhao / Marie-Christine Guiot / Ryan R. Davis / Jeffrey P. Gregg / Christopher Moraes /
    Anne-Claude Gingras / Morag Park

    Cell Reports, Vol 22, Iss 12, Pp 3191-

    2018  Volume 3205

    Abstract: Summary: Triple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. ... ...

    Abstract Summary: Triple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. Here, we show somatic deletion of a region syntenic with human 5q33.2–35.3 in a mouse model of TNBC. Mechanistically, we identify KIBRA as a major factor contributing to the effects of 5q loss on tumor growth and metastatic progression. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro. KIBRA functions co-operatively with the protein tyrosine phosphatase PTPN14 to trigger mechanotransduction-regulated signals that inhibit the nuclear localization of oncogenic transcriptional co-activators YAP/TAZ. Our results argue that the selective advantage produced by 5q loss involves reduced dosage of KIBRA, promoting oncogenic functioning of YAP/TAZ in TNBC. : Triple-negative breast cancers (TNBCs) frequently lose chromosome 5q. Using a TNBC mouse model with spontaneous loss of a syntenic region, Knight et al. identify KIBRA as a metastasis suppressor. Mechanistically, KIBRA suppresses RHOA activation, impairing nuclear translocation of the oncogenes YAP/TAZ, which drive metastatic and cancer stem cell-like behavior. Keywords: KIBRA, WWC1, PTPN14, YAP/TAZ, mechanotransduction, RHOA signaling, triple-negative breast cancer, metastasis, tumorspheres, chr5q
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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