The phospholipase C beta 1 (PLCB1), PLCB4, adenylate cyclase 2 (ADCY2), ADCY8, calcium/calmodulin dependent protein kinase II beta (CAMK2B), CAMK2D, mitogen-activated protein kinase 11 (MAPK11), MAPK14
, epidermal growth factor receptor (EGFR), growth factor receptor bound protein 2 (GRB2), Fyn proto-oncogene, Src family tyrosine kinase (FYN), and integrin subunit beta 5 (ITGB5) genes were involved in 12 significantly enriched pathways and accounted for 0.126% of the genetic variance for MY, 0.109% for FY, and 0.197% for AFC (Supplementary File SI).
Extracellular regulated kinase (ERK) 1/2 (MAPK1/3), P38 (MAPK14
), c-Jun N-terminal kinase (JNK) (MAPK8), and ERK5 (MAPK7) are four components of MAPK pathways. On activation, MAPKs phosphorylate and activate an array of transcription factors that regulate many important physiological and pathological processes in the cell including growth and differentiation, stress, adaptation to the environment, and the inflammatory response.,,,
Sixteen target genes were regulated by more than 1 transcription factor (Table 3), of which the target genes regulated by the most transcription factors were IL-6, MAPK14
, RELA, and FOS, regulated by 4, 3, 3, and 3 TFs, respectively.
The top 10 DEGs with the highest degree included five upregulated DEGs such as estrogen receptor 1 (ESR1), mechanistic target of rapamycin (MTOR), ATM serine/threonine kinase (ATM), CD40 molecule (CD40) and thymidine kinase 2, mitochondrial (TK2), and five downregulated DEGs such as mitogen-activated protein kinase 14 (MAPK14
), phosphatase and tensin homolog (PTEN), intercellular adhesion molecule 1 (ICAM1), aurora kinase A (AURKA), and protein kinase, DNA-activated, catalytic polypeptide (PRKDC) (Table 1).
Cluster 1 includes proteins CASP3, CASP9, BAX, TP53, BAD, GSK3B, POU5F1, MAPK14
, CREB1, SOX2, and KLF4.
The mammalian MAPK family consists of ERK, p38, and JNK with each member having several isoforms: ERK1 to ERK8; p38a (MAPK14
), p38fi (MAPK11), p38g (MAPK12), and p38S (MAPK13); and JNK1 (MAPK8), JNK2 (MAPK9), and JNK3 (MAPK10).
(44) They have shown that miR-17/106 target the mRNA encoding p38 (also known as MAPK14
), which is critical for astrogenesis, suggesting that the miR-17/106-p38 axis plays an important role in the transition of NSCs' fate from neurogenic to astrogenic.
PGF and its downstream MAPK8 and MAPK14
signaling pathways are potential therapeutic targets for the treatment of emphysema and chronic obstructive pulmonary disease (COPD) .
Finally, regulation of some proteins downstream the PI3K has also been related to miRNAs: (1) MTOR and P70S6K1 were proposed to be regulated by reduction of miR-16-5p in obese rats and mice ; (2) MAPK14
expression was related to miR-24-3p in GK rats ; and (3) RAC1 decrease was correlated with miR-23a and miR107 decreasing after weight loss of obese dogs .
demonstrated that extended activation of p21 checkpoint gene triggered mitochondrial dysfunction and formation of ROS through GADD45-p38(MAPK14
)-GRB2-TGFBR2-TGF[beta] signalling pathway .
The MAPK and TNF signaling pathways are anti-inflammatorypathways, with MAPK14
and TNF as the pivotal targets, respectively .
Here, we take kinase GSK3B, PLK1, P38A (MAPK14
), and CDK2 as an example to illustrate the predictive performance, as shown in Figure 2.