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

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) α 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.

[1]  Chao Zhang,et al.  Chemical genetic analysis of the time course of signal transduction by JNK. , 2006, Molecular cell.

[2]  J. Inoue,et al.  Recruitment of Tumor Necrosis Factor Receptor-associated Factor Family Proteins to Apoptosis Signal-regulating Kinase 1 Signalosome Is Essential for Oxidative Stress-induced Cell Death* , 2005, Journal of Biological Chemistry.

[3]  K. Guan,et al.  Identification of FIP200 interaction with the TSC1–TSC2 complex and its role in regulation of cell size control , 2005, The Journal of cell biology.

[4]  J. Guan,et al.  Mechanism of cell cycle regulation by FIP200 in human breast cancer cells. , 2005, Cancer research.

[5]  K. Inoki,et al.  Signaling by Target of Rapamycin Proteins in Cell Growth Control , 2005, Microbiology and Molecular Biology Reviews.

[6]  N. Sonenberg,et al.  Atrophy of S6K1−/− skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control , 2005, Nature Cell Biology.

[7]  H. Ueda,et al.  Overexpression of focal adhesion kinase in vascular endothelial cells promotes angiogenesis in transgenic mice. , 2004, Cardiovascular research.

[8]  H. Okabe,et al.  Expression and regulation of RB1CC1 in developing murine and human tissues. , 2004, International journal of molecular medicine.

[9]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[10]  J. Blenis,et al.  Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression , 2004, Oncogene.

[11]  K. Inoki,et al.  TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival , 2003, Cell.

[12]  Yahong Lin,et al.  A JNK-Dependent Pathway Is Required for TNFα-Induced Apoptosis , 2003, Cell.

[13]  R. Flavell,et al.  JunD mediates survival signaling by the JNK signal transduction pathway. , 2003, Molecular cell.

[14]  L. Cantley,et al.  United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. , 2003, Biochemical Society transactions.

[15]  D. Kwiatkowski,et al.  Tuberous Sclerosis: from Tubers to mTOR , 2003, Annals of human genetics.

[16]  J. Westwick,et al.  The p65/RelA Subunit of NF-κB Suppresses the Sustained, Antiapoptotic Activity of Jun Kinase Induced by Tumor Necrosis Factor , 2002, Molecular and Cellular Biology.

[17]  J. Guan,et al.  EphB1 Associates with Grb7 and Regulates Cell Migration* , 2002, The Journal of Biological Chemistry.

[18]  Hiroki Ueda,et al.  Regulation of focal adhesion kinase by a novel protein inhibitor FIP200. , 2002, Molecular biology of the cell.

[19]  S. Ikegawa,et al.  Truncating mutations of RB1CC1 in human breast cancer , 2002, Nature Genetics.

[20]  D. Goeddel,et al.  TNF-R1 Signaling: A Beautiful Pathway , 2002, Science.

[21]  Hongbing Zhang,et al.  A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. , 2002, Human molecular genetics.

[22]  Nicola Baldini,et al.  Identification of RB1CC1, a novel human gene that can induce RB1 in various human cells , 2002, Oncogene.

[23]  Tetsuo Noda,et al.  A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  T. Jacks,et al.  Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. , 2000, Genes & development.

[25]  R. Kitsis,et al.  The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice , 2000, The EMBO journal.

[26]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[27]  J. Woodgett,et al.  Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation , 2000, Nature.

[28]  H. Ueda,et al.  Suppression of Pyk2 Kinase and Cellular Activities by Fip200 , 2000, The Journal of cell biology.

[29]  T. Mak,et al.  Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. , 2000, Genes & development.

[30]  C. Deng,et al.  Role of the tumor suppressor gene Brca1 in genetic stability and mammary gland tumor formation , 2000, Oncogene.

[31]  H. Onda,et al.  Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. , 1999, The Journal of clinical investigation.

[32]  Inder M. Verma,et al.  Severe Liver Degeneration in Mice Lacking the IκB Kinase 2 Gene , 1999 .

[33]  T. Noda,et al.  Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. , 1999, Cancer research.

[34]  I. Conlon,et al.  Size Control in Animal Development , 1999, Cell.

[35]  K. Miyazono,et al.  ASK1 is essential for JNK/SAPK activation by TRAF2. , 1998, Molecular cell.

[36]  A. Roulston,et al.  Early Activation of c-Jun N-terminal Kinase and p38 Kinase Regulate Cell Survival in Response to Tumor Necrosis Factor α* , 1998, The Journal of Biological Chemistry.

[37]  J. Guan,et al.  Differential Regulation of Pyk2 and Focal Adhesion Kinase (FAK) , 1998, The Journal of Biological Chemistry.

[38]  M. Nussenzweig,et al.  TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival. , 1997, Immunity.

[39]  Dirk Bohmann,et al.  Reduced Ubiquitin-Dependent Degradation of c-Jun After Phosphorylation by MAP Kinases , 1997, Science.

[40]  Michael Karin,et al.  Dissection of TNF Receptor 1 Effector Functions: JNK Activation Is Not Linked to Apoptosis While NF-κB Activation Prevents Cell Death , 1996, Cell.

[41]  F. Alt,et al.  Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Yahong Lin,et al.  A JNK-dependent pathway is required for TNFalpha-induced apoptosis. , 2003, Cell.

[43]  J. Jones,et al.  Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. , 2001, Nature.

[44]  J. Woodgett,et al.  Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. , 2000, Nature.

[45]  I. Verma,et al.  Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. , 1999, Science.

[46]  M. Czaja,et al.  Induction of hepatoma cell apoptosis by c-myc requires zinc and occurs in the absence of DNA fragmentation. , 1996, The American journal of physiology.

[47]  D. Baltimore,et al.  Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. , 1995, Nature.