Synaptopodin-2 induces assembly of peripheral actin bundles and immature focal adhesions to promote lamellipodia formation and prostate cancer cell migration.

Fuiboon Kai,Roy Duncan,James P Fawcett

doi:10.18632/oncotarget.3578

Abstract

Synaptopodin-2 (Synpo2), an actin-binding protein and invasive cancer biomarker, induces formation of complex stress fiber networks in the cell body and promotes PC3 prostate cancer cell migration in response to serum stimulation. The role of these actin networks in enhanced cancer cell migration is unknown. Using time-course analysis and live cell imaging of mock- and Synpo2-transduced PC3 cells, we now show that Synpo2 induces assembly of actin fibers near the cell periphery and Arp2/3-dependent lamellipodia formation. Lamellipodia formed in a non-directional manner or repeatedly changed direction, explaining the enhanced chemokinetic activity of PC3 cells in response to serum stimulation. Myosin contraction promotes retrograde flow of the Synpo2-associated actin filaments at the leading edge and their merger with actin networks in the cell body. Enhanced PC3 cell migration correlates with Synpo2-induced formation of lamellipodia and immature focal adhesions (FAs), but is not dependent on myosin contraction or FA maturation. The previously reported correlation between Synpo2-induced stress fiber assembly and enhanced PC3 cell migration therefore reflects the role of Synpo2 as a newly identified regulator of actin bundle formation and nascent FA assembly near the leading cell edge.

Highlights

The podins are a unique family of proline-rich, actin binding proteins that play important roles in several normal and pathologic cell and tissue processes
Recent results revealed Synpo2 induces formation of ventral stress fiber (SF) in the cell body, the generation of which directly correlates with enhanced PC3 cell migration [17]
We show that Synpo2-induced SF formation in the cell body is an incidental effect of retrograde filamentous actin (F-actin) flow from the cell periphery, and that SF formation reflects the role of Synpo2 as a newly identified effector of actin bundle and lamellipodia formation at the leading cell edge

Summary

Introduction

The podins are a unique family of proline-rich, actin binding proteins that play important roles in several normal and pathologic cell and tissue processes. The founding member of the family, synaptopodin-1 (Synpo1), promotes formation of kidney podocytes and the dendritic spine apparatus of telencephalic synapses [1, 2]. These functions have been linked to Synpo alteration of actin dynamics and cell motility; Synpo regulates filopodia formation [3], α-actinin actin bundling activity [4], and RhoA signaling and stress fiber (SF) biogenesis [2, 5]. Synpo expression, which is predominant in prostate acinar epithelial and basal cells, was dramatically reduced in >92% of invasive prostate cancer tissues, and loss of Synpo expression correlates with prostate cancer relapse [7, 8]. Loss of Synpo expression due to methylationdependent epigenetic silencing of gene expression is associated with invasive bladder cancer [9, 10], suggesting Synpo is a repressor of tumor cell invasion

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