Inki, Finland Full list of author information is available at the end of the articleGAS1 was found to arrest cell cycle by stopping the cells in synthesis (S) phase [1,5] and due to its ability to arrest cell proliferation in p53-dependent manner it has been considered to be a tumour suppressor protein [6,7]. Generally GAS1 might act as a tumour suppressor in adult brain, though the expression in brain leading to apoptosis has not been observed PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/9547713 in adults [3,8]. Sequence comparison of human and murine GAS1 genes suggested that it has a conserved RGD-peptide sequence for possible RGD-dependent integrin binding at residues 306?08 [3]. Additionally GAS1 has been shown to have a significant role in development [9]. At early developmental stages GAS1 is expressed in most embryonic tissues. During development GAS1 has been reported to inhibit?2015 Rosti et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Rosti et al. BMC Biochemistry (2015) 16:Page 2 ofcell proliferation and to mediate cell death, to be involved PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/2100589 in embryonic patterning, and to support growth of the cerebellum [3,8]. GAS1 is clearly a multifunctional protein, since it signals through at least two different kinds of transmembrane receptor proteins, 2H-tridecafluoro-n-octyl)silane 4-Bromo-3-methylbenzaldehyde 2-Bromo-5-methylpyridin-4-amine tert-Butyl (2R)-2-methyl-4-oxopiperidine-1-carboxylate 1-Piperidinecarboxylic acid Rearranged during transformation (RET) [8] and the Hedgehog receptor protein patched-1 [10,11]. The Hedgehog signalling pathway is important in development, stem cell renewal, and cancer progression. GAS1 is able to bind sonic hedgehog (SHH) and activate the signalling pathway from patched-1 [10,11]. RET, on the other hand, is a transmembrane kinase, first identified as a proto-oncogene [12]. Overactivity of RET can cause several types of cancers, and loss-of-function mutations cause varying degrees of loss in the enteric nervous system resulting in Hirschprung’s disease (see e.g. Robertson and Mason [13]). Normally RET mediated signalling is controlled by Glial cell-derived neurotrophic factor family ligands (GFLs) and Glial (E)-1,2-Di(pyridin-4-yl)ethene cell-derived neurotrophic factor receptor alphas (GFRs), which form a four-member protein family (GFR1-4) [14]. Of these, GAS1 has highest (28 ) similarity to GFR1, while GAS1 and GFR4 both have only two domains unlike GFR1-3, which consists of three domains [15]. The secondary structure of mammalian GAS1 is predicted to be mostly -helical separated by short -strands and to have a long unstructured C-terminal domain [15]. By binding GFLs, GFRs take part in controlling the survival of neurons, neuron branching, and functional recovery [14]. The most studied member of GFLs is GDNF, which was identified due to its function as a survival factor for midbrain dopaminergic neurons [14]. GDNF forms a complex with GFR1 and promotes the survival of neurons [16]. GFLs, in general, are dimeric proteins and they are capable of binding two GFR receptors per ligand [14]. After the formation of GFR-GFL complex, the 2-Amino-3-methoxypyridine complex then binds to the transmembrane tyrosine kinase RET [16].Despite the structural similarity to GFRs, GAS1 differs from them functionally because it is able to bind to RET in a liga.