Protein kinase D isoforms differentially modulate cofilin-driven directed cell migration

Heike Döppler, Ligia I. Bastea, Sahra Borges, Samantha J. Spratley, Sarah E. Pearce, Peter Storz

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: Protein kinase D (PKD) enzymes regulate cofilin-driven actin reorganization and directed cell migration through both p21-activated kinase 4 (PAK4) and the phosphatase slingshot 1L (SSH1L). The relative contributions of different endogenous PKD isoforms to both signaling pathways have not been elucidated, sufficiently. Methodology/Principal Findings: We here analyzed two cell lines (HeLa and MDA-MB-468) that express the subtypes protein kinase D2 (PKD2) and protein kinase D3 (PKD3). We show that under normal growth conditions both isoforms can form a complex, in which PKD3 is basally-active and PKD2 is inactive. Basal activity of PKD3 mediates PAK4 activity and downstream signaling, but does not significantly inhibit SSH1L. This signaling constellation was required for facilitating directed cell migration. Activation of PKD2 and further increase of PKD3 activity leads to additional phosphorylation and inhibition of endogenous SSH1L. Net effect is a dramatic increase in phospho-cofilin and a decrease in cell migration, since now both PAK4 and SSH1L are regulated by the active PKD2/PKD3 complex. Conclusions/Significance: Our data suggest that PKD complexes provide an interface for both cofilin regulatory pathways. Dependent on the activity of involved PKD enzymes signaling can be balanced to guarantee a functional cofilin activity cycle and increase cell migration, or imbalanced to decrease cell migration. Our data also provide an explanation of how PKD isoforms mediate different effects on directed cell migration.

Original languageEnglish (US)
Article numbere98090
JournalPLoS One
Volume9
Issue number5
DOIs
StatePublished - May 19 2014

Fingerprint

Actin Depolymerizing Factors
cell movement
protein kinases
Cell Movement
p21-Activated Kinases
Protein Isoforms
4 alpha-glucanotransferase
Phosphorylation
Activity Cycles
Phosphoric Monoester Hydrolases
phosphotransferases (kinases)
Actins
Chemical activation
Cells
protein kinase D
protein kinase C nu
protein kinase D2
D2 protein
Cell Line
Growth

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Protein kinase D isoforms differentially modulate cofilin-driven directed cell migration. / Döppler, Heike; Bastea, Ligia I.; Borges, Sahra; Spratley, Samantha J.; Pearce, Sarah E.; Storz, Peter.

In: PLoS One, Vol. 9, No. 5, e98090, 19.05.2014.

Research output: Contribution to journalArticle

Döppler, Heike ; Bastea, Ligia I. ; Borges, Sahra ; Spratley, Samantha J. ; Pearce, Sarah E. ; Storz, Peter. / Protein kinase D isoforms differentially modulate cofilin-driven directed cell migration. In: PLoS One. 2014 ; Vol. 9, No. 5.
@article{2807ae86111b4570b6d095a9218ceabc,
title = "Protein kinase D isoforms differentially modulate cofilin-driven directed cell migration",
abstract = "Background: Protein kinase D (PKD) enzymes regulate cofilin-driven actin reorganization and directed cell migration through both p21-activated kinase 4 (PAK4) and the phosphatase slingshot 1L (SSH1L). The relative contributions of different endogenous PKD isoforms to both signaling pathways have not been elucidated, sufficiently. Methodology/Principal Findings: We here analyzed two cell lines (HeLa and MDA-MB-468) that express the subtypes protein kinase D2 (PKD2) and protein kinase D3 (PKD3). We show that under normal growth conditions both isoforms can form a complex, in which PKD3 is basally-active and PKD2 is inactive. Basal activity of PKD3 mediates PAK4 activity and downstream signaling, but does not significantly inhibit SSH1L. This signaling constellation was required for facilitating directed cell migration. Activation of PKD2 and further increase of PKD3 activity leads to additional phosphorylation and inhibition of endogenous SSH1L. Net effect is a dramatic increase in phospho-cofilin and a decrease in cell migration, since now both PAK4 and SSH1L are regulated by the active PKD2/PKD3 complex. Conclusions/Significance: Our data suggest that PKD complexes provide an interface for both cofilin regulatory pathways. Dependent on the activity of involved PKD enzymes signaling can be balanced to guarantee a functional cofilin activity cycle and increase cell migration, or imbalanced to decrease cell migration. Our data also provide an explanation of how PKD isoforms mediate different effects on directed cell migration.",
author = "Heike D{\"o}ppler and Bastea, {Ligia I.} and Sahra Borges and Spratley, {Samantha J.} and Pearce, {Sarah E.} and Peter Storz",
year = "2014",
month = "5",
day = "19",
doi = "10.1371/journal.pone.0098090",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Protein kinase D isoforms differentially modulate cofilin-driven directed cell migration

AU - Döppler, Heike

AU - Bastea, Ligia I.

AU - Borges, Sahra

AU - Spratley, Samantha J.

AU - Pearce, Sarah E.

AU - Storz, Peter

PY - 2014/5/19

Y1 - 2014/5/19

N2 - Background: Protein kinase D (PKD) enzymes regulate cofilin-driven actin reorganization and directed cell migration through both p21-activated kinase 4 (PAK4) and the phosphatase slingshot 1L (SSH1L). The relative contributions of different endogenous PKD isoforms to both signaling pathways have not been elucidated, sufficiently. Methodology/Principal Findings: We here analyzed two cell lines (HeLa and MDA-MB-468) that express the subtypes protein kinase D2 (PKD2) and protein kinase D3 (PKD3). We show that under normal growth conditions both isoforms can form a complex, in which PKD3 is basally-active and PKD2 is inactive. Basal activity of PKD3 mediates PAK4 activity and downstream signaling, but does not significantly inhibit SSH1L. This signaling constellation was required for facilitating directed cell migration. Activation of PKD2 and further increase of PKD3 activity leads to additional phosphorylation and inhibition of endogenous SSH1L. Net effect is a dramatic increase in phospho-cofilin and a decrease in cell migration, since now both PAK4 and SSH1L are regulated by the active PKD2/PKD3 complex. Conclusions/Significance: Our data suggest that PKD complexes provide an interface for both cofilin regulatory pathways. Dependent on the activity of involved PKD enzymes signaling can be balanced to guarantee a functional cofilin activity cycle and increase cell migration, or imbalanced to decrease cell migration. Our data also provide an explanation of how PKD isoforms mediate different effects on directed cell migration.

AB - Background: Protein kinase D (PKD) enzymes regulate cofilin-driven actin reorganization and directed cell migration through both p21-activated kinase 4 (PAK4) and the phosphatase slingshot 1L (SSH1L). The relative contributions of different endogenous PKD isoforms to both signaling pathways have not been elucidated, sufficiently. Methodology/Principal Findings: We here analyzed two cell lines (HeLa and MDA-MB-468) that express the subtypes protein kinase D2 (PKD2) and protein kinase D3 (PKD3). We show that under normal growth conditions both isoforms can form a complex, in which PKD3 is basally-active and PKD2 is inactive. Basal activity of PKD3 mediates PAK4 activity and downstream signaling, but does not significantly inhibit SSH1L. This signaling constellation was required for facilitating directed cell migration. Activation of PKD2 and further increase of PKD3 activity leads to additional phosphorylation and inhibition of endogenous SSH1L. Net effect is a dramatic increase in phospho-cofilin and a decrease in cell migration, since now both PAK4 and SSH1L are regulated by the active PKD2/PKD3 complex. Conclusions/Significance: Our data suggest that PKD complexes provide an interface for both cofilin regulatory pathways. Dependent on the activity of involved PKD enzymes signaling can be balanced to guarantee a functional cofilin activity cycle and increase cell migration, or imbalanced to decrease cell migration. Our data also provide an explanation of how PKD isoforms mediate different effects on directed cell migration.

UR - http://www.scopus.com/inward/record.url?scp=84901368594&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901368594&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0098090

DO - 10.1371/journal.pone.0098090

M3 - Article

C2 - 24840177

AN - SCOPUS:84901368594

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e98090

ER -