E3 ubiquitin ligases in regulating stress fiber, lamellipodium, and focal adhesion dynamics

Abstract

Recent discoveries have unveiled the roles of a complicated network of E3 ubiquitin ligases in regulating cell migration machineries. The E3 ubiquitin ligases Smurf1 and Cul/BACURD ubiquitinate RhoA to regulate stress fiber formation and cell polarity, and ASB2α ubiquitinates filamins to modulate cytoskeletal stiffness, thus regulating cell spreading and cell migration. HACE1, XIAP, and Skp1-Cul1-F-box bind to Rac1 and cause its ubiquitination and degradation, thus suppressing lamellipodium protrusions, while PIAS3, a SUMO ligase, activates Rac1 to promote lamellipodium dynamics. Smurf1 also enhances Rac1 activation but it does not ubiquitinate Rac1. Both Smurf1 and HECTD1 regulate focal adhesion (FA) assembly and (or) disassembly through ubiquitinating the talin head domain and phosphatidylinositol 4 phosphate 5-kinase type I γ (PIPKIγ90), respectively. Thus, E3 ubiquitin ligases regulate stress fiber formation, cell polarity, lamellipodium protrusions, and FA dynamics through ubiquitinating the key proteins that control these processes.

Keywords: HACE1; HECTD1; PIP5K1C; Rac1; RhoA.

Figure 1. E3 ubiquitin ligases regulate stress fiber, lamellipodium and focal adhesion dynamics. (1) Both Smurf1 and Cul3/BACURD ubiquitinate RhoA to regulate stress fiber formation and cell polarity, whereas ASB2α ubiquitinates Filamins to modulate the elasticity of the actin network and consequently cell spreading. The activity of Smurf1 is regulated by APC/Cdh1 E3 and CKIP-1. (2) Rac1 is ubiquitinated by a number of E3 ubiquitin ligases, including HACE1, XIAP, and SCF/FBX19, resulting in Rac1 degradation and reduction in lamellipodium extension. On the other hand, sumoylation of Rac1 by PIAS3, a SUMO ligase, stimulates its activation and lamellipodium protrusions. Smurf1-mediated ubiquitination of TRAF4 also promotes Rac1 activation. (3) PIPKIγ90 is ubiquitinated at K97 by HECTD1, resulting its degradation and FA assembly/disassembly during cell migration. Smurf1 binds to TH and causes TH ubiquitination and degradation, consequently leading to FA disassembly.