Signaling-mediated control of ubiquitin ligases in endocytosis - PubMed
- ️Sun Jan 01 2012
Review
Signaling-mediated control of ubiquitin ligases in endocytosis
Simona Polo. BMC Biol. 2012.
Abstract
Ubiquitin-dependent regulation of endocytosis plays an important part in the control of signal transduction, and a critical issue in the understanding of signal transduction therefore relates to regulation of ubiquitination in the endocytic pathway. We discuss here what is known of the mechanisms by which signaling controls the activity of the ubiquitin ligases that specifically recognize the targets of ubiquitination on the endocytic pathway, and suggest alternative mechanisms that deserve experimental investigation.
Figures

Receptor internalization and the role of ubiquitin. The example shown here is that of the EGF receptor. An activated EGFR is ubiquitinated at the plasma membrane and recruits the endocytic adaptor proteins EPS15 and EPSIN-1. These are ubiquitinated, in turn, and direct the internalized receptor to the endosomal pathway where it binds the sorting protein HRS. This is also ubiquitinated and directs progression of the ubiquitinated receptors towards lysosomal degradation through the ESCRT complexes. For simplicity, the EGF receptor is depicted as monoubiquitinated: in reality, it is both multimono- and polyubiquitinated. MVB, multivesicular body.

EGFR ubiquitination by Cbl. Upon EGF-dependent receptor activation, the GRB2-Cbl complex binds to the receptor through interactions of: i) the SH2 domain of GRB2 with pY1045 of EGFR, and ii) the TKB domain of Cbl (either c-Cbl or Cbl-b) with pY1068 or pY1086. This substrate interaction may either stabilize or select for a partially open Cbl conformation (see bottom panel and main text). EGFR-bound Cbl becomes phosphorylated on a critical tyrosine, leading to full rotation of the linker region. This, in turn, exposes the RING domain for ubiquitin-charged E2 binding, resulting in the allosteric activation of the E2 by Cbl and ubiquitination of the EGFR. Note that, to simplify the picture, Cbl bound to one receptor molecule is depicted to ubiquitinate the other molecule of the dimer. No available data suggest that this is indeed the case. For simplicity, the EGF receptor is depicted as monoubiquitinated: in reality, it is both multimono- and polyubiquitinated.

Activation of E3 ubiquitin ligases through recruitment to activated receptors. (a) Ubiquitination of CXCR4 by ITCH. ITCH activity is inhibited as a result of the intramolecular interaction between the WW domain and the carboxy-terminal catalytic HECT domain. Upon agonist-mediated activation, CXCR4 becomes phosphorylated at Ser324 and Ser325 by an unknown kinase. This leads to the recruitment of the ITCH, through its WW domain, and consequent release of the inhibitory intramolecular interaction, allowing ubiquitination of the receptor. (b) Ubiquitination of the TGF-β receptor by the SMURF2-SMAD7 complex. SMURF2 activity is inhibited as a result of the intramolecular interaction between the amino-terminal C2 and the carboxy-terminal catalytic HECT domain. The interaction with SMAD7 NTD displaces the C2 domain of SMURF2 from the HECT domain and activates the ligase. The activated SMURF2-SMAD7 complex associates with activated TGF-β receptor complexes at the membrane via the displaced C2 domain, causing receptor ubiquitination.

Regulation of channels and transporters by ubiquitination. (a) ENaC ubiquitination by NEDD4-2. NEDD4-2 binds to PY motifs on the epithelial Na+ channel ENaC and catalyzes its ubiquitination. This induces ENaC endocytosis and lysosomal targeting, resulting in fewer channels at the cell surface. To increase Na+ transport, NEDD4-2 is phosphorylated by kinases, including PKA, SGK, and IKKβ, in turn activated by various signaling pathways. Phosphorylation of NEDD4-2 induces binding of 14-3-3 dimers (not shown), which prevents NEDD4-2 from binding to ENaC. As a result, endocytosis of ENaC is inhibited, and increased ENaC presence at the surface enhances epithelial Na+ absorption. (b) Rsp5 ubiquitinates permeases and transporters. In yeast, arrestin-related endocytic adaptors (ARTs) and the E3 ubiquitin ligase Rsp5 are recruited to the plasma membrane in response to environmental stimuli that trigger the endocytosis of proteins such as permeases and transporters (for example, the arginine transporter Can1). Through their PY motifs, ARTs bind to the WW domain of Rsp5 and mediate ubiquitination of cargo. ARTs are also ubiquitinated by Rsp5, an event required for endocytosis.

Ubiquitination of adaptors. (a) Agonist induces rapid ubiquitination of GPCR-recruited ARR by MDM2, a process required for receptor internalization. Once internalized, GPCRs can be dephosphorylated and rapidly recycled to the plasma membrane through a mechanism that involves the sorting proteins EBP50 and NSF. (b) Activated EGFR is ubiquitinated at the plasma membrane by Cbl and recruits the UBD-containing endocytic adaptors EPS15 and EPSIN-1 at the plasma membrane, and subsequently HRS at the endosomal membrane. These adaptors, in turn, are ubiquitinated by NEDD4 through a process known as coupled monoubiquitination. This directs progression of the ubiquitinated receptors toward lysosomal degradation through the ESCRT complexes. A similar mechanism can be envisioned for other RTKs.
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