Met-induced membrane blebbing leads to amoeboid cell motility and invasion.

Abstract:

:Met tyrosine kinase has been implicated in tumorigenesis and metastasis; its overexpression and deregulation is often observed in cancer. Although Met's functions in cell motility has been studied extensively, its involvement in bleb-based, amoeboid motility is yet to be determined. The aim of this work is to study the role of Met in amoeboid cell motility and invasion. We show that aggressive breast cancer cells expressing high levels of endogenous Met, as well as HEK293T cells over expressing fluorescent Met, exhibit constitutive, ligand-independent Met activation, leading to Met-dependent membrane blebbing and amoeboid cell motility; HEK293T cells over expressing fluorescent Met were able to invade in three-dimensional matrix. Hyper-activated Met mutant significantly enhances blebbing and cell motility. Met inhibition by either a Met-specific inhibitor or by exogenous expression of a dominant-negative Met remarkably repressed membrane blebbing and invasion. Inhibition of Rho signaling pathway by a ROCK inhibitor also represses Met-induced blebbing, suggesting that Met regulates the blebbing machinery through Rho-ROCK pathway, which controls the actin-myosin contractile force. Either de-polymerization or hyper-polymerization of the actin cytoskeleton abrogates Met-induced blebbing, signifying that actin polymerization has a role in halting and retracting Met-induced mature blebs. Indeed, when blebs retract, membrane wrinkles containing high levels of Met and actin are generated, indicating localized formation of Met-signaling microdomains. We suggest that this bleb-based activity is induced by amplification of Met signaling in unique membrane domains generated by bleb retraction. Our results indicate that Met-induced blebbing has an important role in cell detachment, amoeboid motility and invasion ability, which are utilized by cancer cells for migration and metastasis.

journal_name

Oncogene

journal_title

Oncogene

authors

Laser-Azogui A,Diamant-Levi T,Israeli S,Roytman Y,Tsarfaty I

doi

10.1038/onc.2013.138

subject

Has Abstract

pub_date

2014-04-03 00:00:00

pages

1788-98

issue

14

eissn

0950-9232

issn

1476-5594

pii

onc2013138

journal_volume

33

pub_type

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