title: Mesenchymal chemotaxis requires selective inactivation of myosin II at the leading edge via a noncanonical PLCγ/PKCα pathway.
abstract: Chemotaxis, migration toward soluble chemical cues, is critical for processes such as wound healing and immune surveillance and is exhibited by various cell types, from rapidly migrating leukocytes to slow-moving mesenchymal cells. To study mesenchymal chemotaxis, we observed cell migration in microfluidic chambers that generate stable gradients of platelet-derived growth factor (PDGF). Surprisingly, we found that pathways implicated in amoeboid chemotaxis, such as PI3K and mammalian target of rapamycin signaling, are dispensable for PDGF chemotaxis. Instead, we find that local inactivation of Myosin IIA, through a noncanonical Ser1/2 phosphorylation of the regulatory light chain, is essential. This site is phosphorylated by PKCα, which is activated by an intracellular gradient of diacylglycerol generated by PLCγ. Using a combination of live imaging and gradients of activators/inhibitors in the microfluidic chambers, we demonstrate that this signaling pathway and subsequent inhibition of Myosin II activity at the leading edge are required for mesenchymal chemotaxis.
authors.affiliation: Department of Cell Biology and Physiology, UNC-Chapel Hill, UNC Lineberger Cancer Center, CB7295, Chapel Hill, NC 27599, USA; HHMI, UNC-Chapel Hill, CB7295, Chapel Hill, NC 27599, USA.
authors.forename: Sreeja B
authors.initials: SB
authors.lastname: Asokan
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, Raleigh, NC 27695, USA.
authors.forename: Heath E
authors.initials: HE
authors.lastname: Johnson
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, Raleigh, NC 27695, USA.
authors.forename: Anisur
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Department of Cell Biology and Physiology, UNC-Chapel Hill, UNC Lineberger Cancer Center, CB7295, Chapel Hill, NC 27599, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: King
authors.affiliation: Department of Cell Biology and Physiology, UNC-Chapel Hill, UNC Lineberger Cancer Center, CB7295, Chapel Hill, NC 27599, USA; HHMI, UNC-Chapel Hill, CB7295, Chapel Hill, NC 27599, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Rotty
authors.affiliation: Department of Cell Biology and Physiology, UNC-Chapel Hill, UNC Lineberger Cancer Center, CB7295, Chapel Hill, NC 27599, USA; HHMI, UNC-Chapel Hill, CB7295, Chapel Hill, NC 27599, USA.
authors.forename: Irina P
authors.initials: IP
authors.lastname: Lebedeva
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, Raleigh, NC 27695, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Haugh
authors.affiliation: Department of Cell Biology and Physiology, UNC-Chapel Hill, UNC Lineberger Cancer Center, CB7295, Chapel Hill, NC 27599, USA; HHMI, UNC-Chapel Hill, CB7295, Chapel Hill, NC 27599, USA. Electronic address: jbear@email.unc.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Bear
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis / Q000502:physiology*; D004075:Diglycerides / Q000737:chemistry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D024462:Myosin Type II / Q000378:metabolism*; D010703:Phorbol Esters; D051966:Phospholipase C gamma / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004075:Diglycerides; D008024:Ligands; D010703:Phorbol Esters; D010982:Platelet-Derived Growth Factor; D049452:Green Fluorescent Proteins; D051571:Protein Kinase C-alpha; D051966:Phospholipase C gamma; D024462:Myosin Type II