Ubiquitin-related Molecules in the Akt Pathway Proteins

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Ubiquitin-related Molecules in the Akt Pathway Proteins

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Ubiquitin-related Molecules in the Akt Pathway Proteins Background

Ubiquitination refers to the covalent addition of one or multiple ubiquitin molecules to a target protein via the coordinated actions of ubiquitin-activating (E1) enzymes, ubiquitin-conjugating (E2) enzymes, and ubiquitin ligases (E3s). The Akt pathway is involved in the regulation of many cellular processes, including cell growth, survival, proliferation, autophagy, and metabolism, and is often altered in cancer. Akt is ubiquitinated and deubiquitinated by TRAF-6 and CYLD, respectively, and this ubiquitination appears to be required for the membrane recruitment and activation of Akt. Furthermore, Akt activates MDM2/HDM2, which ubiquitinates and promotes the degradation of the tumor suppressor p53 via the 26S Proteasome. There are many kinds of molecules involved in the ubiquitination process and have been reported to affect or be affected by Akt signaling, such as A20, CYLD and USP8.


A20, also known as TNF-alpha-induced Protein 3 (TNFAIP3) is a 790 amino acid (aa) cytoplasmic protein with a predicted molecular weight of 90 kDa. It was originally described as a protein that is up-regulated by TNF-α stimulation. Human A20/TNFAIP3 showed 88% sequence identity to its mouse ortholog. Structurally, it contains seven zinc finger domains, one of which has ubiquitin ligase (E3) activity. The N-terminus contains a deubiquitinating enzyme (DUB) domain. Therefore, A20/TNFAIP3 can be classified as a bifunctional ubiquitin editing enzyme. It is known to modulate the ability of an inflammatory immune response by acting as a negative feedback regulator of NF-B signaling. Some putative mechanisms include their ability to regulate upstream components of the NF-B pathway, such as RIP1, TRAF2 and TRAF6. Defects in A20/TNFAIP3 are associated with the development of lymphoid malignancies and inflammation and autoimmune diseases.


Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD) is a 956 amino acid (aa) member of the peptidase C67 protein family with a predicted molecular weight of 107 kDa. Mouse and rat CYLD orthologs have 95% and 94% sequence identity to human proteins, respectively. Two CYLD isoforms, a full-length isoform and a second isoform have been identified, lacking a 305-307 due to alternative splicing. The expression of CYLD in the fetal brain as well as in the adult brain, heart, white blood cells, skeletal muscle, spleen and testis has been reported. CYLD acts as a deubiquitinating enzyme and removes K63-linked ubiquitin chains from a variety of substrates including IkB, c-Jun and c-Fos, thereby inhibiting NFkB and JNK signaling. In some cases, CYLD enhances mitotic entry and has been shown to delay G1/S phase entry, indicating that CYLD regulates multiple phases of the cell cycle. CYLD is considered to be a tumor suppressor, and CYLD mutations cause skin-associated syndromes, including Brooke-Spiegle syndrome, familial cylindrical tumor disease, and type 1 familial hair epithelioma.


Ubiquitin Specific Peptidase 8 (USP8), also known as Ubiquitin Isopeptidase Y (UBPY), is a widely expressed deubiquitinating enzyme belonging to the peptidase C19 family. It has a predicted molecular weight of 127.5 kDa. Human USP8 is 1118 amino acids (aa) in length and has 84% sequence identity to mouse and rat orthologs. It contains an N-terminal MIT domain (aa 33-116) that mediates endosome localization, CHMP binding and maintenance of ESCRT-0. USP8 also has a rhodanese domain (aa 181-319) that binds NRDP1 ubiquitin ligase (E3), an SH3 domain binding sequence (aa 405-413) and a C-terminal catalytic domain (aa 734-1110). USP8 is a growth-regulating enzyme that controls the internalization and endocytic transport of cell surface receptors. Some receptors are internalized and degraded by ubiquitination. USP8 has been shown to disrupt the downregulation of multiple receptors by its deubiquitination, including EGFR/ErbB1, ErbB2/Her2 and Smoothened. In contrast, USP8 appears to have an opposite effect on the transport of CXCR4, PAR2 and delta-opioid receptors. Consumption or catalytic inactivation of USP8 stabilizes their expression. It is believed that the deubiquitination of these receptors downstream of the sorted endosomes causes them to enter lysosomal degradation. USP8 can be phosphorylated at Ser680, allowing 14-3-3-epsilon binding, which subsequently inhibits USP8 activity. In addition, USP8 undergoes tyrosine phosphorylation at its N-terminus following EGF activation of the EGFR/ErbB1/ ErbB2/Her2 receptor complex.

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