Adaptor Proteins, Signal Transducing/metabolism* ; Humans

Sequestosome 1 (SQSTM1/p62) is a selective autophagy adaptor protein that plays an important role in the clearance of proteins to be degraded as well as in the maintenance of cellular proteostasis. p62 protein has multiple functional domains, which interact with several downstream proteins to precisely regulate multiple signaling pathways, thereby linking p62 to oxidative defense systems, inflammatory responses and nutrient sensing. Studies have shown that mutation or abnormal expression of p62 is closely related to the occurrence and development of various diseases, including neurodegenerative diseases, tumors, infectious diseases, genetic diseases and chronic diseases. This review summarizes the structural features and molecular functions of p62. Moreover, we systematically introduce its multiple functions in protein homeostasis and regulation of signaling pathways. Furthermore, the complexity and versatility of p62 in the occurrence and development of diseases are summarized, with the aim to provide a reference for understanding the function of p62 protein and facilitating related disease research.
Humans ; Autophagy/genetics* ; Sequestosome-1 Protein/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism* ; Signal Transduction ; Neoplasms/genetics*

Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors (PRRs) to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1, where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/ AP-1 and the signal transducer and activator of transcription 6 (STAT6) to trigger the expression of type I interferons and inflammatory cytokines or the assembly of inflammasomes. Most pleiotropic cytokines are secreted and bind to specific receptors, activating the signaling pathways including JAK-STAT for the proliferation, differentiation and functional capacity of immune cells. This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.
Adaptive Immunity ; Adaptor Proteins, Signal Transducing ; immunology ; metabolism ; Animals ; Humans ; Immunity, Innate ; Signal Transduction ; immunology

YAP/TAZ are wild over-activated in head and neck squamous cell carcinoma (HNSCC) with high potential as a direct therapy target for HNSCC treatments. However, the efforts on the directly targeting-YAP/TAZ therapies over the past decade, have very limited impacts, mainly caused by: 1. There is still none effective and specific YAP/TAZ inhibitor with clinical potential; 2. YAP/TAZ might not be directly targeted, because of their multiple important biological functions, such as: regulation of cell proliferation and survival, stem cell maintain, regulation of organ development, organ size control, and tissue regeneration. Interestingly, the over-activation of YAP/TAZ in HNSCC mainly be regulated by upstream abnormal molecular or biological events, instead of genes alteration of YAP/TAZ. Therefore, exploring the alternative molecular events regulating YAP/TAZ activation and molecular mechanism in HNSCC might help to uncover novel indirect targets of YAP/TAZ therapies for HNSCC prevention and treatment.
Adaptor Proteins, Signal Transducing/metabolism* ; Head and Neck Neoplasms ; Humans ; Phosphoproteins/metabolism* ; Trans-Activators/metabolism* ; Transcription Factors

OBJECTIVE: To explore the interaction between BCL2-associated athanogene 5 (BAG5) and Parkin protein,and the regulatory mechanism of BAG5 protein on the level of Parkin protein. METHODS: We performed GST pull-down assay to identify which domain of PINK1 interacted with Parkin, and generated different deletions of BAG5 to identify the domains. Chase time experiment was done to determine the effect of co-regulation of BAG5 protein on the ubiquitination. We further examined the possible interaction between Parkin and PINK1 in 293A cells by co-immunoprecipitation method. RESULTS: BAG5 directly interacted with the Parkin, and all the 4 BAG domains interacted with the Parkin. BAG5 stabilized the Parkin by interfering its degradation via the ubiquitin-mediated proteasomal pathway. CONCLUSION BAG5 directly interacts with the Parkin, and BAG5 stabilizes the Parkin via the ubiquitin-mediated proteasomal pathway.
Adaptor Proteins, Signal Transducing ; metabolism ; Humans ; Parkinson Disease ; metabolism ; Protein Binding ; Ubiquitin-Protein Ligases ; metabolism ; Ubiquitination

BACKGROUND: Arteriosclerosis obliterans (ASO) is a major cause of adult limb loss worldwide. Autophagy of vascular endothelial cell (VEC) contributes to the ASO progression. However, the molecular mechanism that controls VEC autophagy remains unclear. In this study, we aimed to explore the role of the GRB2 associated binding protein 1 (GAB1) in regulating VEC autophagy. METHODS: In vivo and in vitro studies were applied to determine the loss of adapt protein GAB1 in association with ASO progression. Histological GAB1 expression was measured in sclerotic vascular intima and normal vascular intima. Gain- and loss-of-function of GAB1 were applied in VEC to determine the effect and potential downstream signaling of GAB1. RESULTS: The autophagy repressor p62 was significantly downregulated in ASO intima as compared to that in healthy donor (0.80 vs. 0.20, t = 6.43, P < 0.05). The expression level of GAB1 mRNA (1.00 vs. 0.24, t = 7.41, P < 0.05) and protein (0.72 vs. 0.21, t = 5.97, P < 0.05) was significantly decreased in ASO group as compared with the control group. Loss of GAB1 led to a remarkable decrease in LC3II (1.19 vs. 0.68, t = 5.99, P < 0.05), whereas overexpression of GAB1 significantly led to a decrease in LC3II level (0.41 vs. 0.93, t = 7.12, P < 0.05). Phosphorylation levels of JNK and p38 were significantly associated with gain- and loss-of-function of GAB1 protein. CONCLUSION Loss of GAB1 promotes VEC autophagy which is associated with ASO. GAB1 and its downstream signaling might be potential therapeutic targets for ASO treatment.
Adaptor Proteins, Signal Transducing ; Adult ; Arteriosclerosis Obliterans/genetics* ; Autophagy ; GRB2 Adaptor Protein ; Humans ; Phosphoproteins/metabolism* ; Phosphorylation ; Protein Binding ; Signal Transduction

Epidermal growth factor receptor pathway substrate 8 (Eps8) is one of crucial kinase substrates for the epidermal growth factor receptors. Eps8 is related to mitosis and differentiation of normal cells. In recent years, it has been demonstrated that Eps8 involves in proliferation, metastasis and prognosis of many malignant tumors. Experiments have shown that Eps8 involves in Ras-Rac pathway of EGFR signaling by forming Eps8-Abi1-Sos1 tri-complex or participates in endocytosis mediated by rab5. Furthermore, Eps8 has also been found to regulate cell cycle. In conclusion, it may become a monitor and a new target for the treatment of malignant tumors. This review briefly introduces molecular structure and physiological function of Eps8, focusing on its function and molecular mechanism in proliferation, metastasis and prognosis of malignant tumors.
Adaptor Proteins, Signal Transducing ; metabolism ; Humans ; Neoplasm Metastasis ; Neoplasms ; metabolism ; pathology ; Prognosis

In the central nervous system, nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS). In the past 20 years, the studies in our group and other laboratories have suggested a significant involvement of nNOS in a variety of neurological and neuropsychiatric disorders. In particular, the interactions between the PDZ domain of nNOS and its adaptor proteins, including post-synaptic density 95, the carboxy-terminal PDZ ligand of nNOS, and the serotonin transporter, significantly influence the subcellular localization and functions of nNOS in the brain. The nNOS-mediated protein-protein interactions provide new attractive targets and guide the discovery of therapeutic drugs for neurological and neuropsychiatric disorders. Here, we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.
Humans ; Nitric Oxide Synthase Type I/metabolism* ; Adaptor Proteins, Signal Transducing ; Brain/metabolism* ; Nervous System Diseases

Dysregulation of the Wnt pathway has been extensively studied in multiple diseases, including some angiogenic disorders. Wnt signaling activation is a major stimulator in pathological angiogenesis and thus, Wnt antagonists are believed to have therapeutic potential for neovascular disorders. Actually, some Wnt antagonists have been identified directly from the anti-angiogenic factor family. This review summarizes the recent progress toward understanding of the roles of Wnt pathway antagonists in angiogenic regulation and their mechanism of action, and exploring their therapeutic potential.
Adaptor Proteins, Signal Transducing ; metabolism ; Animals ; Humans ; Neovascularization, Pathologic ; physiopathology ; Repressor Proteins ; metabolism ; Signal Transduction ; physiology ; Wnt Proteins ; antagonists & inhibitors

The aim of this study was to observe the inhibitory effect of daunorubicin on KG1a cells and the expression of Eps8 which is a novel tumor-associated antigen with its full name epidermal growth factor receptor pathway substrate 8 (Eps8), and to explore the effect of daunorubicin on Eps8 expression in KG1a cells at mRNA and protein levels. The KG1a cells were treated with different concentration of daunorubicin for 24, 48, 72 h, then trypan blue staining was used to detect the inhibitory rate of KGla cells, RQ-PCR and Western blot were used to detect Eps8 mRNA and Eps8 protein expression. The results showed that daunorubicin inhibited the proliferation of KG1a cells in a dose and time dependent manner (r = 0.983, P < 0.01). Daunorubicin could reduce the mRNA and protein levels of Eps8 expression in dose and time dependent manners in KG1a cells (r = 0.979, P < 0.05). It is concluded that with the increasing of concentration and time of daunorubicin acting on KG1a cells, the cell proliferative inhibitory effect increased and the expression of Eps8 decreased, suggesting that the inhibitory effect of daunorubicin on KG1a cell proliferation is realized through downregulation of Eps8 expression.
Adaptor Proteins, Signal Transducing ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Daunorubicin ; pharmacology ; Humans