PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions

Abstract

The Rac1 activator Tiam1 is inhibited by internal interactions. Phosphorylation of Tiam1 by aPKC lends bias to an “open” conformation, potentiating its activation and allowing for its localization through protein–protein interactions.

The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

“…Full-length Tiam1 (residue 1-1591) GEF activity is auto-inhibited (32). The N50 of full-length Tiam1 inhibits its localization and GEF activity through an interaction with the PH n -CC-Ex domain and, to a lesser extent, with the DH-PH c domain (33). However, it is not known whether other structured domains participate in the auto-inhibition of Tiam1.…”

“…However, studies in cells show that the PH c subdomain has an important effect on GEF activity through interactions with the membrane (50,51). Moreover, the N-terminal most 50 amino acids (N50) of Tiam1 inhibit its GEF activity by directly binding the PH n -CC-Ex domain and to a lesser extent the catalytic DH-PH c domain (33). Nevertheless, observations that Tiam1 can be activated by protein interactions through the PH n -CC-Ex and RBD domains and phosphorylation (Tyr-829) suggest that there may be additional levels of inhibition (21,25,27,32).…”

“…Early cell biological studies of Tiam1 revealed that truncation of ϳ400 amino acids of the N terminus promoted GEF activity (10,32,55). The origin of this auto-inhibition was recently determined to be the N-terminal 50 amino acids (N50), which contains an aPKC␥ phosphorylation site (33). The authors proposed a model whereby Tiam1 is biased in a closed, auto-inhibited state through the interaction of the N50 region and the PH n -CC-Ex domain.…”

“…These studies and previous observations (10,32) suggest that the N terminus of Tiam1 is autoinhibitory. Indeed, a recent study by Kaibuchi and co-workers (33) showed that the first 50 residues at the N terminus (N50) inhibited Tiam1 GEF function by binding to the PH n -CC-Ex domain and, to a lesser extent, the catalytic DH-PH c domain. Furthermore, phosphorylation of serine residues within N50 by the aPKC␥ kinase relieved auto-inhibition.…”

Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity

“…We further show that the requirement of PI3K activity is upstream of Tiam1, the action of both proteins is required for apical membrane remodeling, and PI3K and Tiam1 act synergistically to reinforce membrane changes. Par3 has been implicated in both the activation and suppression of Rac1 activity (Chen and Macara, 2005; Zhang and Macara, 2006; Pegtel et al , 2007; Mack et al , 2012; Matsuzawa et al , 2016); our work suggests that Par3 tethers Tiam1 to specific cellular locations and then relies on the local protein environment to dictate whether Rac1 is activated or repressed. It is also remarkable that targeting Tiam1 and PI3K to the apical membrane could drive membrane remodeling, and expression of both proteins had a synergistic effect on apical membrane remodeling.…”