# SEA and GATOR 10 Years Later
###### Abstract  
The SEA complex was described for the first time in yeast _Saccharomyces cerevisiae_ ten years ago, and its human homologue GATOR complex two years later. During the past decade, many advances on the SEA/GATOR biology in different organisms have been made that allowed its role as an essential upstream regulator of the mTOR1 pathway to be defined. In this review, we describe these advances in relation to the identification of multiple functions of the SEA/GATOR complex in nutrient response and beyond and highlight the consequence of GATOR mutations in cancer and neurodegenerative diseases.  
SEA complex; GATOR complex; mTOR1 pathway; autophagy; amino acid signaling; cancer; epilepsy; neurological disorders +
Footnote †: journal: Cells  
e lect. 10 Years Later. 2021 10. 2689.  
and Ybl104p [5]. Four years later, in 2011, a paper that described the full SEA complex for the first time was published [3]. The four proteins, which were first observed in Seh1 pullouts in 2007, were given a common name, Sea (for Seh1-associated) and named Sea1 through Sea4, respectively. The following three other protein components completed the full SEA eight-protein complex: Sec13, Npr2 and Npr3. The proteins of the SEA complex appeared to be dynamically associated with the vacuole membrane and have a role in autophagy. The function of Iml1-Npr2-Npr3 in autophagy was also described by the Tu group that same year [9]. Meanwhile, in 2009, Npr2 and Npr3 were shown to form an evolutionary conserved heterodimer, involved in the upstream regulation of TORC1 in response to amino acid starvation in _S. cerevisiae_[10]. This fundamental function of the SEA complex was further confirmed both in yeast and humans by [PERSON] and [PERSON] laboratories in 2013 [11; 12].  
The SEA complex in _S. cerevisiae_ consists of two subcomplexes, named SEACIT (SEA subcomplex inhibiting TORC1) and SEACAT (SEA subcomplex activating TORC1) (see below) [11; 13; 14] (Figure 1). In 2013, these complexes were characterized for the first time in humans by [PERSON]'s laboratory and were re-named to GATOR1 (GTPase activating protein activity toward RAGA, see below) and GATOR2, respectively [12]. SEACIT is composed of Iml1/Sea1, Npr2 and Npr3 (DEPDC5, NPRL2 and NPRL3 in GATOR1), and SEACAT contains Sea2, Sea3, Sea4, Seh1 and Sec13 (WDR24, WDR59, MMOS, SEHIL, SEC13 in GATOR2) (Figure 1).  
Phylogenetic analyses demonstrated that SEA/GATOR complex subunits are present across various eukaryotic kingdoms, suggesting an origin of these factors before the last common eukaryotic ancestor [3]. Homologs of all eight proteins could be clearly found in the genomes of fungi and metazoans, with some representation in protists, but cannot be identified in plants [3; 15]. In 2021, the homologs of the SEA complex and its components were characterized in _Schizosaccharomyces pombe_[16], _Caenorhabditis elegans_[17], _Drosophila_[18], zebrafish [19], mice [20], rats [21] and humans [12]. The  
Figure 1: Composition of yeast SEA complex and mammalian GATOR complex. SEACIT subcomplex in yeast can tightly interact with SEACAT, most probably via Npr3/Sea3 connection. GATOR1 and GATOR2 do not form a stable full GATOR complex.  
majority of the structural and functional studies were usually performed in _S. cerevisiae_ and in humans. _Drosophila_ was very instrumental for the study of the SEA/GATOR role in development; while the zebrafish, mouse and rat models were used to study different human pathologies.