Abl Kinases Regulate HGF/Met Signaling Required for Epithelial Cell Scattering, Tubulogenesis and Motility.

Ran Li,Ann Marie Pendergast,Morag Park,Jennifer F Knight,Andrea Morrione

doi:10.1371/journal.pone.0124960

Ran Li, Ann Marie Pendergast + Show 3 more

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https://doi.org/10.1371/journal.pone.0124960

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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.

Highlights

Receptor tyrosine kinases (RTKs) regulate processes required for normal mammalian development and tissue homeostasis, and aberrant RTK function promotes numerous pathological conditions including cancer [1]
As hepatocyte growth factor (HGF) is known to cause scattering of Madin Darby canine kidney (MDCK) cells, we examined the role of Abl kinases in this process using two distinct pharmacological inhibitors of the Abl kinases: STI571 (Imatinib/Gleevec) and GNF2, which bind to the ATP binding site and C-terminal myristoyl group binding site, respectively [35, 36]
We found that knockdown or pharmacological inhibition of the Abl kinases markedly decreased HGF-induced cell scattering, actomyosin bundles and branching tubule formation in MDCK epithelial cells

Summary

Introduction

Receptor tyrosine kinases (RTKs) regulate processes required for normal mammalian development and tissue homeostasis, and aberrant RTK function promotes numerous pathological conditions including cancer [1]. Among these RTKs, the hepatocyte growth factor (HGF) receptor, Met, regulates vertebrate cellular responses including proliferation, survival, motility, invasion and morphogenesis required for normal physiological functions during embryogenesis and in the adult [1, 2]. Enhanced HGF/Met signaling is a characteristic feature of many solid tumors and is associated with therapy resistance [1,2,3,4]. Up-regulation of HGF/Met signaling may occur through MET amplification, transcriptional activation, Met protein kinase.

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