Syndecan-4 Phosphorylation Is a Control Point for Integrin Recycling

Mark R Morgan,Hellyeh Hamidi,Mark D Bass,Stacey Warwood,Christoph Ballestrem,Martin J Humphries

doi:10.1016/j.devcel.2013.01.027

Mark R Morgan, Hellyeh Hamidi + Show 4 more

Open Access

https://doi.org/10.1016/j.devcel.2013.01.027

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Abstract

SummaryPrecise spatiotemporal coordination of integrin adhesion complex dynamics is essential for efficient cell migration. For cells adherent to fibronectin, differential engagement of α5β1 and αVβ3 integrins is used to elicit changes in adhesion complex stability, mechanosensation, matrix assembly, and migration, but the mechanisms responsible for receptor regulation have remained largely obscure. We identify phosphorylation of the membrane-intercalated proteoglycan syndecan-4 as an essential switch controlling integrin recycling. Src phosphorylates syndecan-4 and, by driving syntenin binding, leads to suppression of Arf6 activity and recycling of αVβ3 to the plasma membrane at the expense of α5β1. The resultant elevation in αVβ3 engagement promotes stabilization of focal adhesions. Conversely, abrogation of syndecan-4 phosphorylation drives surface expression of α5β1, destabilizes adhesion complexes, and disrupts cell migration. These data identify the dynamic spatiotemporal regulation of Src-mediated syndecan-4 phosphorylation as an essential switch controlling integrin trafficking and adhesion dynamics to promote efficient cell migration.

Highlights

Haptotactic migration, in which cells are guided by direct interactions of adhesion receptors with extracellular matrix (ECM) fibers, is fundamental to tissue morphogenesis, homeostasis, and repair and for the pathogenesis of inflammatory and neoplastic diseases
We demonstrate that syndecan-4 is the major control point that regulates integrin recycling to coordinate Focal adhesions (FAs) dynamics and cell migration. c-Src-mediated syndecan-4 phosphorylation is shown to regulate Arf6 activity, via modulation of syntenin binding, and acts as a molecular switch to determine directly whether a5b1 or aVb3 integrins are delivered to the membrane
It has been reported that syndecan-4 is tyrosine phosphorylated and that this modification is sensitive to treatment with broadspectrum tyrosine kinase inhibitors (Ott and Rapraeger, 1998)

Summary

Introduction

Haptotactic migration, in which cells are guided by direct interactions of adhesion receptors with extracellular matrix (ECM) fibers, is fundamental to tissue morphogenesis, homeostasis, and repair and for the pathogenesis of inflammatory and neoplastic diseases. The fibronectin-binding integrins a5b1 and aVb3 exhibit distinct biomechanical, mechanoresponsive, and signaling properties that directly influence the dynamic interaction with the ECM and cell migration (Danen et al, 2002, 2005; Hu et al, 2007; Puklin-Faucher and Sheetz, 2009; RocaCusachs et al, 2009). It follows that, during cell migration in vivo, heterodimer-specific integrin localization at the cell-ECM interface must be tightly regulated. Elucidating the precise mechanisms that control heterodimer-specific trafficking of integrins, and how this process modulates FA dynamics, is fundamental to understanding how cell migration is coordinated

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