Diacylglycerol kinase alpha mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI.
Diacylglycerol kinases (DGKs) convert diacylglycerol (DAG) into phosphatidic acid (PA), acting as molecular switches between DAG- and PA-mediated signaling. We previously showed that Src-dependent activation and plasma membrane recruitment of DGKalpha are required for growth-factor-induced cell migration and ruffling, through the control of Rac small-GTPase activation and plasma membrane localization. Herein we unveil a signaling pathway through which DGKalpha coordinates the localization of Rac. We show that upon hepatocyte growth-factor stimulation, DGKalpha, by producing PA, provides a key signal to recruit atypical PKCzeta/iota (aPKCzeta/iota) in complex with RhoGDI and Rac at ruffling sites of colony-growing epithelial cells. Then, DGKalpha-dependent activation of aPKCzeta/iota mediates the release of Rac from the inhibitory complex with RhoGDI, allowing its activation and leading to formation of membrane ruffles, which constitute essential requirements for cell migration. These findings highlight DGKalpha as the central element of a lipid signaling pathway linking tyrosine kinase growth-factor receptors to regulation of aPKCs and RhoGDI, and providing a positional signal regulating Rac association to the plasma membrane.
Chianale
Federica
F
Department of Clinical and Experimental Medicine and Biotecnologie per la Ricerca Medica Applicata, University Amedeo Avogadro of Piemonte Orientale, 28100 Novara, Italy.
Rainero
Elena
E
Cianflone
Cristina
C
Bettio
Valentina
V
Pighini
Andrea
A
Porporato
Paolo E
PE
Filigheddu
Nicoletta
N
Serini
Guido
G
Sinigaglia
Fabiola
F
Baldanzi
Gianluca
G
Graziani
Andrea
A
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D004285:Dogs; D005455:Fluorescent Antibody Technique; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D020730:Guanine Nucleotide Dissociation Inhibitors; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D017228:Hepatocyte Growth Factor; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D020744:rac GTP-Binding Proteins