Cell Biology

A New Role for SODD with SKIP and PIP3

Science Signaling  30 Aug 2011:
Vol. 4, Issue 188, pp. ec243
DOI: 10.1126/scisignal.4188ec243

Phosphatidylinositol 3,4,5-trisphosphate (PIP3) recruits the serine/threonine kinase Akt to the plasma membrane, leading to Akt activation, thereby promoting F-actin polymerization and cell migration. Using skeletal muscle and kidney enriched inositol 5-phosphatase (SKIP) as bait in yeast two-hybrid assays, Rahman et al. identified an interaction with SODD (silencer of death domains, named for its association with death domains of specific tumor necrosis factor receptor superfamily members). In vitro binding assays using recombinant SKIP and SODD confirmed a direct interaction between the two proteins, which also colocalized at the plasma membrane of epidermal growth factor (EGF)–stimulated COS-7 cells. SKIP’s 5-phosphatase activity was increased in mouse embryo fibroblasts (MEFs) derived from SODD-deficient mice (SODD–/–) compared with that in SODD+/+ MEFs or SODD–/– MEFs expressing FLAG-tagged SODD, indicating that SODD repressed SKIP’s activity. Activation of Akt, as determined by immunoblotting for Akt phosphorylated at Ser473 and Thre308, was decreased in EGF-stimulated SODD–/– MEFs relative to EGF-stimulated wild-type MEFs, as was the amount of polymerized F-actin and actin stress fiber network exhibited by cells, as indicated by phalloidin staining. Expression of constitutively active myristoylated Akt in SODD–/– MEFs, however, increased the amount of polymerized F-actin, in comparison with nontransfected neighboring SODD–/– MEFs. Together, the results suggest that SODD enhances PIP3-mediated signaling to the actin cytoskeleton through Akt by repressing SKIP inositol polyphosphate 5-phosphatase activity.

P. Rahman, R. D. Huysmans, F. Wiradjaja, R. Gurung, L. M. Ooms, D. A. Sheffield, J. M. Dyson, M. J. Layton, A. Sriratana, H. Takada, T. Tiganis, C. A. Mitchell, Silencer of death domains (SODD) inhibits skeletal muscle and kidney enriched inositol 5-phosphatase (SKIP) and regulates phosphoinositide 3-kinase (PI3K)/Akt signaling to the actin cytoskeleton. J. Biol. Chem. 286, 29758–29770 (2011). [Abstract] [Full Text]