C-Abl Kinase Is a Regulator of αvβ3 Integrin Mediated Melanoma A375 Cell Migration

Chunmei Zhang,Chao Yang,Xianlu Zeng,Yang Jiao,Ruifei Wang,Khamal Kwesi Ampah,Xiaoguang Wang,Chih-Hsin Tang

doi:10.1371/journal.pone.0066108

Chunmei Zhang, Chao Yang + Show 6 more

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https://doi.org/10.1371/journal.pone.0066108

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Abstract

Integrins are heterodimeric transmembrane receptors that physically link the extracellular matrix (ECM) to the intracellular actin cytoskeleton, and are also signaling molecules that transduce signals bi-directionally across the plasma membrane. Integrin regulation is essential for tumor cell migration in response to growth factors. c-Abl kinase is a nonreceptor tyrosine kinase and is critical for signaling transduction from various receptors. Here we show that c-Abl kinase is involved in A375 cell migration mediated by αvβ3 integrin in response to PDGF stimulation. c-Abl kinase colocalizes with αvβ3 integrin dynamically and affects αvβ3 integrin affinity by regulating its cluster. The interaction between c-Abl kinase and αvβ3 integrin was dependent on the activity of c-Abl kinase induced by PDGF stimulation, but was not dependent on the binding of αvβ3 integrin with its ligands, suggesting that c-Abl kinase is not involved in the outside-in signaling of αvβ3 integrin. Talin head domain was required for the interaction between c-Abl kinase and αvβ3 integrin, and the SH3 domain of c-Abl kinase was involved in its interaction with talin and αvβ3 integrin. Taken together, we have uncovered a novel and critical role of c-Abl kinase in αvβ3 integrin mediated melanoma cell migration.

Highlights

The metastatic sequence of tumor cells is understood to involve detachment of cell within primary tumor, local migration and intravasating into the bloodstream, and extravasating into tissue, further local crawling, migration and invasion, generation of new colonies
We demonstrated that c-Abl kinase was involved in avb3 integrin mediated A375 cell migration induced by PDGF
To determine the roles of these two integrins in the migration induced by PDGF, avb3 and b1 were respectively blocked with antibodies in the migration assay

Summary

Introduction

The metastatic sequence of tumor cells is understood to involve detachment of cell within primary tumor, local migration and intravasating into the bloodstream, and extravasating into tissue, further local crawling, migration and invasion, generation of new colonies. They mediate signal transduction through the cell membrane in both directions: binding of ligands to integrins transmits signals into the cell and results in cytoskeletal re-organization, gene expression and cellular differentiation (outside-in signaling); on the other side, signals from within the cell (in response to local stimuli) can propagate through integrins and regulate integrin ligand-binding affinity and cell adhesion (inside-out signaling) [7,8]. This bidirectional signaling is mainly mediated by the short cytoplasmic tails of the two integrin subunits [9]. The increase of migration in tumor cell is due in part to integrin avb3 [10,11]

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