PMID:17015619

Citation	Gan, B, Peng, X, Nagy, T, Alcaraz, A, Gu, H and Guan, JL (2006) Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways. J. Cell Biol. 175:121-33
Abstract	Focal adhesion kinase family interacting protein of 200 kD (FIP200) has been shown to regulate diverse cellular functions such as cell size, proliferation, and migration in vitro. However, the function of FIP200 in vivo has not been investigated. We show that targeted deletion of FIP200 in the mouse led to embryonic death at mid/late gestation associated with heart failure and liver degeneration. We found that FIP200 knockout (KO) embryos show reduced S6 kinase activation and cell size as a result of increased tuberous sclerosis complex function. Furthermore, FIP200 KO embryos exhibited significant apoptosis in heart and liver. Consistent with this, FIP200 KO mouse embryo fibroblasts and liver cells showed increased apoptosis and reduced c-Jun N-terminal kinase phosphorylation in response to tumor necrosis factor (TNF) alpha stimulation, which might be mediated by FIP200 interaction with apoptosis signal-regulating kinase 1 (ASK1) and TNF receptor-associated factor 2 (TRAF2), regulation of TRAF2-ASK1 interaction, and ASK1 phosphorylation. Together, our results reveal that FIP200 functions as a regulatory node to couple two important signaling pathways to regulate cell growth and survival during mouse embryogenesis.
Links	PubMed PMC2064504 Online version:10.1083/jcb.200604129
Keywords	Animals; Apoptosis; Cell Size; Embryo, Mammalian/cytology; Embryo, Mammalian/metabolism; Embryonic Development/physiology; Enzyme Activation; Fetal Death; Gene Deletion; Gestational Age; Heart/embryology; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Intracellular Signaling Peptides and Proteins/physiology; JNK Mitogen-Activated Protein Kinases/metabolism; Liver/cytology; Liver/embryology; Liver/metabolism; MAP Kinase Kinase Kinase 5/metabolism; Mice; Myocardium/cytology; Myocardium/metabolism; Protein Kinases/metabolism; Ribosomal Protein S6 Kinases/metabolism; Signal Transduction; TNF Receptor-Associated Factor 2/metabolism; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha/metabolism; Tumor Suppressor Proteins/metabolism
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