TOM1-like protein 1 (TOM1L1) is an adapter protein involved in signaling pathways. It interacts with the SH2 and SH3 domains of various signaling proteins when it is phosphorylated. TOM1L1 promotes activation of Src family tyrosine kinase Fyn, possibly by disrupting intramolecular SH3-dependent interactions [].
Tom1 (target of Myb 1) and its related proteins (Tom1L1 and Tom1L2) constitute a protein family and share an N-terminal VHS (Vps27p/Hrs/Stam) domain followed by a GAT (GGA and Tom1) domain.VHS domains are found at the N termini of select proteins involved in intracellular membrane trafficking and are often localized to membranes. The three dimensional structure of human TOM1 VHS domain reveals eight helices arranged in a superhelix. The surface of the domain has two main features: (1) a basic patch on one side due to several conserved positively charged residues on helix 3 and (2) a negatively charged ridge on the opposite side, formed by residues on helix 2 []. The basic patch is thought to mediate membrane binding.It was demonstrated that the GAT domain of both Tom1 and Tom1L1 binds ubiquitin, suggesting that these proteins might participate in the sorting of ubiquitinated proteins into multivesicular bodies (MVB) []. Moreover, Tom1L1 interacts with members of the MVB sorting machinery. Specifically, the VHS domain of Tom1L1 interacts with Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), whereas a PTAP motif, located between the VHS and GAT domains of Tom1L1, is responsible for binding to TSG101 (tumour susceptibility gene 101). Myc epitope-tagged Tom1L1 is recruited to endosomes following Hrs expression. In addition, Tom1L1 possesses several tyrosine motifs at the C-terminal region that mediate interactions with members of the Src family kinases and other signalling proteins such as Grb2 and p85. Expression of a constitutively active form of Fyn kinase promotes the recruitment of Tom1L1 to enlarged endosomes. It is proposed that Tom1L1 could act as an intermediary between the signalling and degradative pathways [].Over expression of Tom1 suppresses activation of the transcription factors NF-kappaB and AP-1, induced by either IL-1beta or tumour necrosis factor (TNF)-alpha, and the VHS domain of Tom1 is indispensable for this suppressive activity. This suggests that Tom1 is a common negative regulator of signalling pathways induced by IL-1beta and TNF-alpha [].
Tollip (Toll-interacting protein) is a component of the IL-1RI pathway which contains an N-terminal C2 domain and a C-terminal CUE domain. Tollip binds to the cytoplasmic TIR domain of IL-1Rs after IL-1 stimulation. It is sufficient for recruitment of IRAK to IL-1Rs and negatively regulates IL-1-induced signaling by inhibiting IRAK phosphorylation. In addition, Tollip directly interacts with toll-like receptors TLR2 and TLR4, and plays an inhibitory role in TLR-mediated cell activation through suppressing phosphorylation and kinase activity of IRAK. Moreover, Tollip can associate with GAT domains of Tom1 and its related proteins Tom1L1 and Tom1L2, and facilitate the recruitment of clathrin onto endosomes [, ].
