A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors

HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed in many human tissues, both adult and fetal. It is important to understand the role of HER4 in the treatment of many disorders. Many studies were also conducted on the role of HER4 in tumors and its tumor suppressor function. Mostly, overexpression of HER4 kinase results in cancer development. In the present article, we reviewed the structure, location, ligands, physiological functions of HER4, and its relationship to different cancer types. HER4 inhibitors reported mainly from 2016 to the present were reviewed as well.

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Recent Advances in the Role of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 in Breast and Ovarian Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.747314 ◽

2021 ◽

Vol 9 ◽

Author(s):

Li Chen ◽

Xiangyi Kong ◽

Yi Fang ◽

Shishir Paunikar ◽

Xiangyu Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Tyrosine Kinase ◽

Ligand Binding ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Kinase Activity ◽

Receptor Tyrosine Kinases ◽

Breast And Ovarian Cancer ◽

Discoidin Domain Receptor

Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.

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TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00711-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xueer Wang ◽

Honghai Zhang ◽

Zhugui Shao ◽

Wanxin Zhuang ◽

Chao Sui ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Fungal Pathogen ◽

Essential Role ◽

Molecular Mechanisms ◽

Systemic Infection ◽

Lectin Receptors ◽

Innate And Adaptive Immunity ◽

Cytokines And Chemokines

AbstractSpleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31−/− mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

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