TY - JOUR
T1 - Daydreamer, a Ras effector and GSK-3 substrate, is important for directional sensing and cell motility
AU - Koelsch, Verena
AU - Shen, Zhouxin
AU - Lee, Susan
AU - Plak, Katarzyna
AU - Lotfi, Pouya
AU - Chang, Jessica
AU - Charest, Pascale G.
AU - Romero, Jesus Lacal
AU - Jeon, Taeck J.
AU - Kortholt, Arjan
AU - Briggs, Steven P.
AU - Firtel, Richard A.
PY - 2013/1/15
Y1 - 2013/1/15
N2 - How independent signaling pathways are integrated to holistically control a biological process is not well understood. We have identified Daydreamer (DydA), a new member of the Mig10/RIAM/lamellipodin (MRL) family of adaptor proteins that localizes to the leading edge of the cell. DydA is a putative Ras effector that is required for cell polarization and directional movement during chemotaxis. dydA(-) cells exhibit elevated F-actin and assembled myosin II (MyoII), increased and extended phosphoinositide-3-kinase (PI3K) activity, and extended phosphorylation of the activation loop of PKB and PKBR1, suggesting that DydA is involved in the negative regulation of these pathways. DydA is phosphorylated by glycogen synthase kinase-3 (GSK-3), which is required for some, but not all, of DydA's functions, including the proper regulation of PKB and PKBR1 and MyoII assembly. gskA(-) cells exhibit very strong chemotactic phenotypes, as previously described, but exhibit an increased rate of random motility. gskA- cells have a reduced MyoII response and a reduced level of phosphatidylinositol (3,4,5)-triphosphate production, but a highly extended recruitment of PI3K to the plasma membrane and highly extended kinetics of PKB and PKBR1 activation. Our results demonstrate that GSK-3 function is essential for chemotaxis, regulating multiple substrates, and that one of these effectors, DydA, plays a key function in the dynamic regulation of chemotaxis.
AB - How independent signaling pathways are integrated to holistically control a biological process is not well understood. We have identified Daydreamer (DydA), a new member of the Mig10/RIAM/lamellipodin (MRL) family of adaptor proteins that localizes to the leading edge of the cell. DydA is a putative Ras effector that is required for cell polarization and directional movement during chemotaxis. dydA(-) cells exhibit elevated F-actin and assembled myosin II (MyoII), increased and extended phosphoinositide-3-kinase (PI3K) activity, and extended phosphorylation of the activation loop of PKB and PKBR1, suggesting that DydA is involved in the negative regulation of these pathways. DydA is phosphorylated by glycogen synthase kinase-3 (GSK-3), which is required for some, but not all, of DydA's functions, including the proper regulation of PKB and PKBR1 and MyoII assembly. gskA(-) cells exhibit very strong chemotactic phenotypes, as previously described, but exhibit an increased rate of random motility. gskA- cells have a reduced MyoII response and a reduced level of phosphatidylinositol (3,4,5)-triphosphate production, but a highly extended recruitment of PI3K to the plasma membrane and highly extended kinetics of PKB and PKBR1 activation. Our results demonstrate that GSK-3 function is essential for chemotaxis, regulating multiple substrates, and that one of these effectors, DydA, plays a key function in the dynamic regulation of chemotaxis.
KW - GLYCOGEN-SYNTHASE KINASE-3
KW - DEPENDENT PROTEIN-KINASE
KW - RABBIT SKELETAL-MUSCLE
KW - DICTYOSTELIUM-DISCOIDEUM
KW - MEDIATES CHEMOTAXIS
KW - ACTIN CYTOSKELETON
KW - SIGNALING PATHWAYS
KW - STAT PROTEIN
KW - ACTIVATION
KW - POLARITY
U2 - 10.1091/mbc.E12-04-0271
DO - 10.1091/mbc.E12-04-0271
M3 - Article
C2 - 23135995
SN - 1059-1524
VL - 24
SP - 100
EP - 114
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
IS - 2
ER -