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Two new anchoring factors, GSKIP and GSK3beta join to strengthen cAMP/PKA/Drp1 axis signaling under oxidative stress (LB221)
Author(s) -
Hong YiRen
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb221
Subject(s) - forskolin , phosphorylation , microbiology and biotechnology , chemistry , mutant , gsk 3 , mitochondrion , biology , receptor , biochemistry , gene
Two new anchoring factors, GSKIP and GSK3beta join to strengthen cAMP/PKA/Drp1 axis signaling under oxidative stress Yi‐Ren Hong 1 1 Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan We firstly demonstrated that PKA, GSKIP, GSK3β and Drp1 form a working complex which similar to proclaimed cAMP/PKA/Drp1 axis that has been linked to elongated mitochondrial morphology (JBC, 2007; Nat Cell Biol, 2011). This finding raises a question about whether GSKIP and GSK3β as mediators of cAMP/PKA/Drp1 axis signaling. Our data demonstrated that overexpressed GSKIP and its mutants, Drp1 Ser637 enhanced phosphorylation 7~8‐fold in the GSKIP wt group compared to both defective mutant groups in a temporal manner under H 2 O 2 and forskolin challenge, implicating both V41/L45 (PKA RII binding) and L130 (GSK3β binding) are important to the Drp1‐associated protective action of GSKIP. In addition, our data also imply that GSK3β may act as a scaffold protein that recruits Drp1 for PKA, directly phosphorylating at Ser637. We therefore silenced either of GSKIP or of GSK3β and resulted in a dramatic decrease of Drp1 Ser637 phosphorylation, indicating that both GSKIP‐ and GSK3 plays as anchoring protein in this novel PKA/GSKIP/GSK3/Drp1 complex. By using confocal fluorescent microscopy, only GSKIP wt, but not V41/L45 or L130 mutant, exhibited elongated mitochondrial morphology after compromising the effects of H 2 O 2 and forskolin. Taken together, in addition to involvement in neurite outgrowth, our data illustrated a new role for GSKIP, associated with acquired resistance to H 2 O 2 ‐induced apoptosis through influencing mitochondrial morphology by coordinating both the activation of PKA‐mediated Drp1 phosphorylation at Ser637 and tethering GSK3β to recruit Drp1 by anchoring rather than by kinase activity.