Roles of E3 ubiquitin ligases in cell adhesion and migration

Abstract

Recent studies have demonstrated that a number of E3 ubiquitin ligases, including Cbl, Smurf1, Smurf2, HDM2, BCA2, SCF(beta-TRCP) and XRNF185, play important roles in cell adhesion and migration. Cbl negatively regulates cell adhesion via alpha integrin and Rap1 and inhibits actin polymerization by ubiquitinating mDab1 and WAVE2. Smurf1 regulates cell migration through ubiquitination of RhoA, talin head domain and hPEM2, while Smurf2 ubiquitinates Smurf1, TGFbeta type I receptor and RaplB to modulate cell migration and adhesion. HDM2 negatively regulates cell migration by targeting NFAT (a transcription factor) for ubiquitination and degradation, while SCF(beta-TRCP) ubiquitinates Snail (a transcriptional repressor of E-cadherin) to inhibit cell migration. TRIM32 promotes cell migration through ubiquitination of Abl interactor 2 (Abi2), a tumor suppressor. RNF5 and XRNF185 modulate cell migration by ubiquitinating paxillin. Thus, these E3 ubiquitin ligases regulate cell adhesion and (or) migration through ubiquitination of their specific substrates.

Figure 1

Domain structures of the Cbl family members in mammals. Both c-Cbl and Cbl-b have a tyrosine kinase binding (TKB) domain, a C3HC4 Zinc-binding RING finger (RF) domain, a proline-rich region and a leucine zipper (LZ) domain. A ubiquitin-associated (UBA) domain overlaps with the LZ domain. Cbl-c has a TKB domain, a C3HC4 RF domain and a very short proline-rich region. C-Cbl has four major tyrosine phosphorylation sites: Tyr³⁷¹, Tyr⁷⁰⁰, Tyr⁷³¹ and Tyr⁷⁷⁴, whereas Cbl-b is phosphorylated at Tyr⁶⁵⁵ and Tyr⁷⁰⁹. Currently identified major binding partners for each domain (or region) are also listed.

Figure 2

Cbl regulates cell adhesion and migration. Cbl targets α5 integrin, CrkL and FAK for ubiquitination thus suppressing integrin activation and cell adhesion. It also negatively regulates actin polymerization by ubiquitinating mDab1 and Wave2 and downregulates growth factor receptors, such as EGFR, PDGFR, Met and Kit, by ubiquitinating the receptors to induce cell polarization.

Figure 3

Domain structures of Smurf1 and Smurf2. Smurf1 has an amino terminal C2 domain, two WW domains and a catalytic carboxyl terminal HECT domain. A nuclear export signal (NES) sequence (I⁶⁰⁶G-GLDKIDL⁶¹⁴) localizes in the carboxyl terminus of Smurf1. Smurf2 has an amino terminal C2 domain, three WW domains and a catalytic carboxyl terminal HECT domain.

Figure 4

Smurfs regulate cell adhesion and migration. Smurf1 ubiquitinates RhoA and hPEM-2, thus inhibiting actin polymerization and regulating cell protrusions. It also regulates focal adhesion dynamics and cell migration through targeting talin head domain for ubiquitination and degradation. Smurf2 mediates Rap1B ubiquitination and is implicated in integrin suppression, and promotes cell polarization and migration by ubiquitinating TGFβR. in addition, it may ubiquitinate Smurf1.