title: Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells.
abstract: The cyclical protrusion and retraction of the leading edge is a hallmark of many migrating cells involved in processes such as development, inflammation and tumorigenesis. The molecular identity of the signalling mechanisms that control these cycles has remained unknown. Here, we used live-cell imaging of biosensors to monitor spontaneous morphodynamic and signalling activities, and employed correlative image analysis to examine the role of cyclic-AMP-activated protein kinase A (PKA) in protrusion regulation. PKA activity at the leading edge is closely synchronized with rapid protrusion and with the activity of RhoA. Ensuing PKA phosphorylation of RhoA and the resulting increased interaction between RhoA and RhoGDI (Rho GDP-dissociation inhibitor) establish a negative feedback mechanism that controls the cycling of RhoA activity at the leading edge. Thus, cooperation between PKA, RhoA and RhoGDI forms a pacemaker that governs the morphodynamic behaviour of migrating cells.
authors.affiliation: Department of Medicine, University of California San Diego, 9500 Gilman Drive, Mail Code 0726, La Jolla, California 92093, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Tkachenko
authors.forename: Mohsen
authors.initials: M
authors.lastname: Sabouri-Ghomi
authors.forename: Olivier
authors.initials: O
authors.lastname: Pertz
authors.forename: Chungho
authors.initials: C
authors.lastname: Kim
authors.forename: Edgar
authors.initials: E
authors.lastname: Gutierrez
authors.forename: Matthias
authors.initials: M
authors.lastname: Machacek
authors.forename: Alex
authors.initials: A
authors.lastname: Groisman
authors.forename: Gaudenz
authors.initials: G
authors.lastname: Danuser
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004173:Dipodomys; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology*; D005260:Female; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000201:enzymology; D051381:Rats; D015398:Signal Transduction; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020730:Guanine Nucleotide Dissociation Inhibitors; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases; D020742:rhoA GTP-Binding Protein