Endocytosis of TRAM (TICAM2)

Stable Identifier
Homo sapiens
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TRIF-related adapter molecule (TRAM or also known as TICAM2) is a sorting adapter which recruits TRIF to activated TLR4. Like TLR4, TRAM (TICAM2) was detected both at the plasma membrane and in the endosomal compartment. TICAM2 was reported to recruit TRIF to the plasma membrane (Tanimuro N et al. 2008). However, TICAM2 did not induce TRIF-mediated signaling from the cell surface, instead, TICAM2 endocytosis was required for activation of IRF3 and induction of IFN-beta (Tanimuro N et al. 2008; Kagan JC et al. 2008). Although, endocytosis of both TLR4 and TICAM2 and their association are required to trigger TRIF-mediated signaling, TICAM2 can target endosomes independently on its interaction with TLR4. TICAM2 cellular localization is controlled by myristoylation and phosphorylation of its N-terminal bipartite sorting signal motif (Kagan JC et al 2008).

TICAM2 has been shown to undergo phosphorylation on Ser-16 by protein kinase C (PKC) epsilon in LPS-treated human THP1 and murine embryonic fibroblasts (MEF) cells (McGettrick AF et al. 2006). The phosphorylation at Ser-16 by PKC epsilon was required for TICAM2 to be depleted from the membrane (McGettrick AF et al. 2006).

It has recently been demonstrated that phosphorylation of TICAM2 at tyrosine residue Y167 by an unknown protein tyrosine kinase is needed for TICAM2 translocation from the plasma membrane to the endosomal membrane, where it can associate with the activated TLR4 complex (Huai et al. 2015). PTPN4, a protein tyrosine phosphatase, dephosphorylates Y167 of TICAM2, thus inhibiting TICAM2 endocytosis (Huai et al. 2015).

Literature References
PubMed ID Title Journal Year
18222170 Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling

Akashi-Takamura, S, Matsumoto, F, Miyake, K, Tanimura, N, Saitoh, S

Biochem Biophys Res Commun 2008
25825441 Phosphatase PTPN4 preferentially inhibits TRIF-dependent TLR4 pathway by dephosphorylating TRAM

Zhao, J, Huai, W, Li, B, Song, H, Jiang, G, Zhang, L, Zhao, W, Wang, L, Han, L, Gao, C

J. Immunol. 2015
16757566 Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling

Fitzgerald, KA, O'Neill, LA, Palsson-McDermott, EM, Brint, EK, Rowe, DC, Gay, NJ, Golenbock, DT, McGettrick, AF

Proc Natl Acad Sci U S A 2006
18297073 TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta

Horng, T, Kagan, JC, Su, T, Akira, S, Chow, A, Medzhitov, R

Nat Immunol 2008
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