EGFR signaling pathway occupies an important position in cancer‐related downstream signaling pathways of Pyk2

Abstract

Proline‐rich tyrosine kinase 2 (Pyk2) is a member of focal adhesion kinase (FAK) non‐receptor tyrosine kinase family and has been found to promote cancer cell survival, proliferation, migration, invasion, and metastasis. Pyk2 takes part in different carcinogenic signaling pathways to promote cancer progression, including epidermal growth factor receptor (EGFR) signaling pathway. EGFR signaling pathway is a traditional carcinogenic signaling pathway, which plays a critical role in tumorigenesis and tumor progression. FAK inhibitors have been reported to fail to get the ideal anti‐cancer outcomes because of activation of EGFR signaling pathway. Better understanding of Pyk2 downstream targets and interconnectivity between Pyk2 and carcinogenic EGFR signaling pathway will help finding more effective targets for clinical anti‐cancer combination therapies. Thus, the interconnectivity between Pyk2 and EGFR signaling pathway, which regulates tumor development and metastasis, needs to be elucidated. In this review, we summarized the downstream targets of Pyk2 in cancers, focused on the connection between Pyk2 and EGFR signaling pathway in different cancer types, and provided a new overview of the roles of Pyk2 in EGFR signaling pathway and cancer development.

Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells

“…Our findings demonstrated that pepsin, in vitro, at slightly acidic pH of 6.0 and in particular at neutral pH of 7.0 preserves cell survival and induces activation of specific oncogenic markers clinically associated with HNSCC [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 51 , 53 ]. Despite the possible pepsin-related stress toxicity and damage in cancer hypopharyngeal cells at either pH 7.4 or pH 7.0 [ 21 , 24 ], using our model, we provide evidence of the oncogenic effect of pepsin in normal HCs at pH 7.0 or 6.0, in line with other observations by Johnston’s team [ 6 , 25 ].…”

“…Elucidating the mechanism of the effect of pepsin on HCs, we showed the abundant activation of EGFR, which was documented by a significant overexpression of phospho-EGFR and EGFR mRNAs, accompanied by activation of two more oncogenic factors, NF- κ B and STAT3, and a significant upregulation of genes linked to related oncogenic signaling pathways, such as EGFR/AKT1/mTOR , TNF-α/RELA(p65)/BCL2 , STAT3 and cancer-related cytokines, IL6 and IL1β . It is known that EGFR activation can exert an oncogenic effect by activating downstream oncogenic pathways, such as AKT/mTOR, STAT3 and NF- κ B [ 39 , 40 , 41 , 42 , 44 ], strongly supporting the role EGFR as a key molecule of the pepsin-induced tumorigenic effect on the hypopharynx in a less acidic environment.…”

“… The effect of pepsin on epidermal growth factor receptor (EGFR) and its related signalling pathway in human hypopharyngeal primary cells, at less acidic LPR. Pepsin at slightly acidic or neutral pH causes significant overexpression of EGFR, accompanied by elevated activation of p-NF- κ B and p-STAT3, and a significant overexpression of EGFR-related oncogenic factors and cytokines, including AKT1, mTOR , IL1β , IL6, TNF-α , STAT3 and RELA(p65), and antiapoptotic BCL2 , previously linked to HNSCC [ 35 , 36 , 39 , 40 , 41 , 42 , 46 , 47 , 48 , 52 ]. (red arrows: pepsin effect in HCs; dashed black arrows: possible interactions; green boxes: genes upregulated by pepsin).…”

“…EGFR is a transmembrane glycoprotein and is activated through the binding of epidermal growth factor and other ligands. After its activation, receptor dimerization, and autophosphorylation, EGFR stimulates a downstream of several oncogenic signaling pathways such as AKT, mTOR, NF- κ B, and STAT3 [ 39 , 40 , 41 , 42 , 43 , 44 ]. Van Waes’s team has also demonstrated EGFR overexpression in the HNSCC cell line and suggested that EGFR signaling activates NF- κ B related pathways and downstream genes [ 45 ].…”

13-Butoxyberberine Bromide Inhibits Migration and Invasion in Skin Cancer A431 Cells

“…When EGFR was activated, proliferation, differentiation, transformation, angiogenesis, migration, and survival of cancer cells were induced [ 9 ]. Phosphorylation of EGFR activates the downstream components including ERK, PI3K/Akt, and STAT signaling pathways [ 10 ], which play a crucial role in cancer metastasis [ 11 ]. In addition, several studies reported that the EGFR signaling pathway also regulated MMP expression [ 12 , 13 ].…”