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Role of FIP200 in cardiac and liver development and its regulation of TNF and TSC–mTOR signaling pathways

¹ Department of Molecular Medicine and ² Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853
³ Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
⁴ Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, NY 10032

Correspondence to Jun-Lin Guan: jlguan{at}umich.edu

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) 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.

Abbreviations used in this paper: 4EBP1, 4E binding protein 1; ASK1, apoptosis signal–regulating kinase 1; CC, coiled-coil region; CT, C-terminal region; E, embryonic day; ES, embryonic stem; FIP200, FAK family interacting protein of 200 kD; KO, knockout; MKK, MAPK kinase; MEF, mouse embryo fibroblast; mTOR, mammalian target of rapamycin; RB1CC1, RB1-inducible coiled-coil 1; S6K, S6 kinase; TNFR, TNF receptor; TRAF2, TNFR-associated factor 2; TRITC, tetramethyl rhodamine isothiocyanate; TSC, tuberous sclerosis complex; WGA, wheat germ agglutinin; WT, wild-type.

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