ReviewFIP200, a key signaling node to coordinately regulate various cellular processes
Introduction
During metazoan development, the increase of cell size and number and thus the growth of an organ or organism are coordinately regulated by several important biological processes, including cell growth, cell proliferation and cell survival/death. Cell size is regulated by cell growth, whereas cell number is determined by the balance between cell proliferation and cell survival/death [1]. Cell growth is a prerequisite for cell proliferation during normal organ growth, and sustained cell proliferation must be coupled to appropriate cell growth. With appropriate cell growth, a net increase in cell number in a growing organ depends on the rate at which they are generated by cell proliferation and eliminated by cell death. Furthermore, cell spreading and migration also play important roles in multiple processes during metazoan development, including embryogenesis, wound healing, angiogenesis and inflammatory immune response [2]. Perturbation of these processes could lead to malformation or embryonic death, as well as a variety of diseases in adult life, such as cancer. In contrast to our understanding of the molecular mechanisms that regulate these cellular processes, relatively less is known about the mechanisms of how these cellular processes are coordinately regulated during the development of an organism.
FIP200 (FAK-family Interacting Protein of 200 kDa) has emerged from recent studies as a critical signaling node to coordinately regulate cell growth, cell proliferation, cell survival and cell spreading/migration. There is also increasing evidence that dysregulation of FIP200 is linked to embryonic death and cancer development in adult life. Here, we focus on our current understanding of FIP200 signaling pathway, with an emphasis on the diverse cellular functions and interacting proteins regulated by FIP200. We will then explore the emerging roles of FIP200 in embryogenesis and cancer development. Finally, we will identify and discuss the important questions remaining to be addressed.
Section snippets
FIP200 gene expression, protein structure and subcellular localization
FIP200 was initially identified as a Pyk2 interacting protein through yeast two-hybrid screen in our laboratory in 2000 [3]. FIP200 was shown to inhibit Pyk2 kinase activity and negatively regulate Pyk2 functions [3]. In 2002, FIP200 has also been independently identified as a potential regulator of the RB1 gene (designated by this group as RB1CC1 for RB1-inducible coiled-coil 1) by Dr. Chano and his colleagues [4]. Prior to these studies, the full length cDNA for FIP200 was already isolated
FIP200 function in various cellular processes
So far, totally 8 proteins have been identified as FIP200 interacting proteins, including stathmin [6], Pyk2 [3], FAK [13], ActA [7], p53 [14], TSC1 [11], [15], ASK1 and TRAF2 [12] (Table 1). It should be noted that not all FIP200 interacting proteins have been confirmed at the endogenous level and therefore the significance of some interactions should be more rigorously studied. Nevertheless, this short list of interacting proteins provides us valuable information about FIP200 function. It
The role of FIP200 in embryonic development
FIP200 is abundantly expressed throughout mouse embryonic development [10], suggesting that FIP200 might play an important role in embryogenesis. To study the potential function of FIP200 in embryogenesis, we recently generated FIP200 KO mouse. Targeted deletion of FIP200 in the mouse leads to embryonic death at mid/late gestation associated with heart failure and liver degeneration [12]. The heart ventricular wall in FIP200 KO embryos at E14.5 and E15.5 loses much of the normal trabecular and
The potential role of FIP200 in cancer development
Human FIP200 gene localizes in 8q11 chromosome, a region containing several loci of putative tumor suppressor genes, and loss of heterozygosity (LOH) of this region has been associated with various human cancers, including breast cancer [48], [49]. It was found that 20% (7 of 35) of primary breast cancers that were screened contain large deletion mutations in FIP200 that are predicted to generate markedly truncated proteins lacking the NLS, the leucine zipper motif and the coiled-coil region
Future prospects
Over the past several years, the important role of FIP200 in coordinating signaling pathways has emerged. However, much remains to be learned about the exact biochemical and cellular functions of FIP200 and its connection to human diseases. This review intends to summarize our current view of FIP200 signaling, identify important questions and provide guidance for future studies. Since many questions have been raised and discussed throughout the review, only a few will be highlighted here.
Acknowledgements
This work is supported by NIH grant GM52890 to JL Guan. We thank our colleagues Huijun Wei, Huaping Fan, Fei Liu, Chun-Chi Liang and Heui Jin Ho for critical reading and helpful suggestions.
References (59)
- et al.
Cell
(1999) - et al.
Cell
(1996) - et al.
Gene
(2002) - et al.
Am. J. Pathol.
(2002) - et al.
Cell. Signal.
(2000) Cell
(2000)- et al.
Mol. Cell
(1998) - et al.
Immunity
(1997) - et al.
Cell
(2000) - et al.
Cell
(2006)
Cancer Cells
Eur. J. Cancer
J. Biol. Chem.
Curr. Opin. Cell Biol.
Cell
Cell
J. Cell. Biol.
Oncogene
Proc. Natl. Acad. Sci. U. S. A.
Cell. Microbiol.
Int. J. Mol. Med.
J. Cell Biol.
J. Cell Biol.
Mol. Biol. Cell
Cancer Res.
Int. J. Mol. Med.
J. Cell Biol.
EMBO Rep.
Cited by (62)
mTOR signaling and autophagy regulation
2023, Autophagy Processes and MechanismsThe emerging roles of ATG1/ATG13 kinase complex in plants
2022, Journal of Plant PhysiologyCitation Excerpt :FIP200 promotes Atg1 kinase activity in mammals and Drosophila (Ganley et al., 2009; Nagy et al., 2014). ATG101 is not conserved in S. cerevisiae (Chano et al., 2002; Gan and Guan, 2008). The mammalian ATG101 directly binds to ATG13 and prevents proteasomal degradation of the ATG1/ATG13 complex (Hosokawa et al., 2009; Mercer et al., 2009).
Autophagy Blockade Limits HER2+ Breast Cancer Tumorigenesis by Perturbing HER2 Trafficking and Promoting Release Via Small Extracellular Vesicles
2021, Developmental CellCitation Excerpt :While it is possible that autophagy may play opposing roles in different subtypes of breast cancer, an emerging hypothesis is that some of the effects are due to the loss of their non-autophagy functions. Besides its well-characterized role in autophagy, FIP200 has been shown to interact with other proteins to regulate diverse cellular functions (Gan and Guan, 2008). Likewise, Beclin1 has been shown to control p53 levels through regulation of the deubiquitination activity of USP10 and USP13, which may contribute to its tumor-suppressive function independent of or in addition to its role in autophagy (Liu et al., 2011).
Mechanistic Insights into the Role of Atg11 in Selective Autophagy
2020, Journal of Molecular BiologyDifferent patterns of allelic imbalance in sporadic tumors and tumors associated with long-term exposure to gamma-radiation
2015, Mutation Research - Genetic Toxicology and Environmental Mutagenesis