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.
Although our knowledge of FIP200 downstream signaling pathways has increased considerably recently, virtually nothing is known about how FIP200 is regulated by upstream stimuli. Is the expression level of FIP200 or its phosphorylation status, protein stability, subcellular localization regulated by certain signaling, especially those in which FIP200 has been shown to play a role, such as cell adhesion, nutrient or growth factor signaling? If so, what is the underlying biochemical mechanism? Addressing these questions should provide critical insight into how FIP200 functions to coordinate various signaling pathways. In this regard, other genomics and proteomics studies might provide unbiased and important information of FIP200 regulation. A recent study applied the powerful mass spectrometric technology to study global in vivo
phosphoproteome and its temporal dynamics upon growth-factor stimulation and has identified more than 6000 phosphorylation sites on 2000 or so proteins upon EGF stimulation [59
]. Intriguingly, this study identified 6 phosphorylation sites in FIP200, at least one of which is strongly regulated by EGF stimulation. The phosphorylation sites can be further predicted to be phosphorylated by kinases such as GSK3 and PKA [59
]. Although the identity and functional significance of these phosphorylation events need to be further confirmed, it provides strong evidence that FIP200 is tightly regulated by growth factor-mediated phosphorylation signaling events.
Second, our current knowledge of FIP200 is largely built upon in vitro studies and its in vivo relevance needs more rigorous investigation. The related questions for future studies include whether FIP200 indeed functions as a bona fide tumor suppressor, whether FIP200 play any role in the regulation of atrophy/hypertrophy based on its function in the regulation of mTOR signaling and cell growth, whether FIP200 regulates FAK signaling and cancer metastasis in vivo. Generation and analysis of various tissue specific KO mice models and compound mutant mice by crossing with other mice models will allow a critical determination of the in vivo functions of FIP200.
Finally, numerous studies from other model organisms, including yeast, worm and fly, have provided incredible insight into the protein functions in human and the molecular mechanisms of human diseases, including cancer development. Since FIP200 is an evolutionarily conserved protein present in worm and fly, utilization of these model organisms in the future study would be of vital importance in deciphering FIP200 function. We expect that there would be many exciting breakthroughs elucidating the mechanism of FIP200 signaling and its implications in human diseases in the foreseeable future.