INTRODUCTION:

Mitogen-activated protein kinases are a type of serine-threonine kinases or MAPKs, facilitate intracellular signalling linked to a range of cellular processes like cell division, multiplication, subsistence, and transformation.^1,2 We give some background information on MAPK pathways in this overview, followed by a discussion of significant discoveries that point to potential routes connecting MAPKs to certain disorders. MAPKs are widely distributed components of signalling pathways that regulate the activity of cells.^3,4 MAPKs be phosphorylated and activated by MAP2Ks, that further activates as well as phosphorylated by MAP3Ks.

Substrate protein, many transcriptions factor like Elke-1, c-Jun, ATF2, and p53, get phosphorylated by active MAPKs. MAPK Pathways can be activated by either a sequence of binary interactions between kinase components or the formation of a signaling complex including numerous kinases directed by a scaffold protein. The scaffold proteins are makin' it easy for the kinase component activate the MAPK signal path. β-Arrestin 2 functions as a scaffold protein for the signalling pathways of ERK and JNK.^5,6 TNF-α and IL-1 β, two proinflammatory cytokines, alongside cellular stressors like oxidative, hypoxic, osmotic, genotoxic stress, been said to have the capability to the JNK as well as p38 signalling pathways.⁷

The JNK pathway's MAP3Ks, especially ASK1 and TAK1, also activate p38 through the p38 signalling pathway, where different MAP2Ks like MKK3 and MKK6 activate p38.Certain MAP2Ks, such as MKK3 and MKK6, they are stimulating p38 in the path of the p38 signaling. These MAP3Ks, like ASK1 and TAK1, they are also responsibles for the activation of p38 within the pathway of the JNK. Raf1 (or C-Raf), an isomer of Raf (A-, B-, or Raf1), stimulates either ERK1 or ERK2, and then MEK1/2 activates ERK1/2. The activation of the small GTPase Ras occurs through the RTK-Grb2-SOS signaling pathway, which subsequently triggers the activation of the Raf-1 kinases.² Members of the Ras family, including K-Ras, H-Ras, and N-Ras, play a crucial role in transmitting extracellular signals into cells, facilitating key cellular responses.⁸ In addition to being a MAP3K that may phosphorylate a MAP2K in the JNK or ERK signaling cascades, MEKK1 is also a potential source of E3 ubiquitin ligase activity. To control cell adhesion and migration, MEKK1 interacts with a variety of proteins, including actin, Rac, and RhoA.⁹ In mice lacking MEKK1, lung metastases and tumour cell dispersion were seen to be significantly postponed.¹⁰ The JNK and p38 signaling pathways rely on a group of enzymes called MAP3Ks, with apoptosis signal-regulating kinase 1 (ASK1) playing a key role. ASK1 gets activated in response to different stress signals, including a rise in calcium levels, exposure to lipopolysaccharide (LPS), oxidative stress, and disruptions in the endoplasmic reticulum (ER).¹¹

MAPK pathway role in polyscystic ovary syndrome:

If the delicate balance between cyclic nucleotides and ERK1/2 activity is disrupted, it can result in the misbehavior of these kinases, which can worsen the progression of diseases. Cyclic nucleotide concentrations affect the susceptibility of ERK1/2 to stimuli based on cell state, including division status, interactions with neighbouring cells, and hormone, growth factor, and cytokine levels.^12,13 MAPKs can significantly alter the patterns of gene transcription, resulting in either over- or under-expression of important proteins. Additionally, through the epithelial-mesenchymal transition, for example, they may cause a lack the of epithelial cells and the growth of smooth muscle cells.^14,15 The mechanisms that integrate cAMP to ERK1/2 inputs are not entirely known. Understanding the interactions between ERK1/2 and cAMP is particularly significant in the context of polycystic kidney disease (PKD) because of its clinical implications. Loss of polycystin is the most prevalent cause of PKD.^1,2 When these components are taken out of the cilia of kidney epithelial cells, the way that these cells signal is altered. Cilia participate in the ERK1/2 cascade and are able to identify growth factors and other signals in a variety of cells. Polycystin 1 regulates Polycystin 2, a non-selective cation channel present in cilia. Intracellular calcium levels, maintained by polycystins. ERK1/2 restrict development in healthy kidneys in response to elevated cAMP levels. In PKD, increased cAMP levels trigger proliferation mediated by ERK1/2, leading to cyst development and epithelial polarity loss.^16,20 Inhibiting the ERK1/2 pathway reduces aberrant proliferation. Vasopressin stimulates kidney cells, leading to increased fluid reabsorption and cAMP levels because of this Kidney cells regularly experience high cAMP levels. The relationship between cAMP and the ERK1/2 pathway in normal renal cells has been demonstrated to be altered by adjusting intracellular calcium, simulating the aberrant signaling seen in PKD.¹⁶

MAPK pathway role in Cancer:

In the ERK signalling pathway two proteins are involved that are Ras and B-Raf and have been linked to several cancer-associated alterations in MAPK signalling system components.^2,21 Human malignancies, such as those of the lung and colon, commonly include mutations of K-Ras.²² It is true that over 50% of colon tumours have K-Ras mutations, although N-Ras mutations are uncommon in these cases.⁸ Transgenic animals expressing activated K-Ras (G12D) have increased colonic epithelial cell proliferation in a MEK-dependent way; this effect is not observed in transgenic mice expressing N-Ras (G12D). This suggests that, in contrast to N-Ras (G12D), K-Ras (G12D) increases the MEK-ERK signaling pathway and promotes colonic epithelial cell proliferation.^23,24 MEK1/2 activation increases the synthesis of matrix metalloproteinase and shields cancer cells from anoikis, or separation-induced apoptosis.²⁵ Approximately 66% of malignant melanomas are caused by alterations in the B-Raf gene.²⁶ The most common mutation in B-Raf is V600E, where valine is replaced by glutamate, leading to constant activation of B-Raf and the ERK signaling pathway.²⁷ B-Raf mutations, even those that don't impact its own kinase activity, can enhance MEK-ERK signaling by pairing with Raf-1.²⁸ Acute myeloid leukaemia also has mutations in the Raf-1 gene.²⁹ Multiple stages of tumor development are influenced by the ERK signalling pathway. Proteins that ERK phosphorylates to facilitate cancer cell motility include focused adhesion kinase, paxillin, myosin light chain kinase, and calpain.³⁰ Additionally, the ERK pathway stimulates the production of matrix metalloproteinases, which facilitates extracellular matrix protein breakdown and subsequent tumour invasion.³¹ ERK1/2 signaling regulates Bcl-2 family proteins like BIM (pro-apoptotic) and MCL-1 (anti-apoptotic), controlling their levels and activity to influence cancer cell survival.³² Therefore, ERK facilitates the phosphorylation of the transcription factor FOXO3A, which results in the proteasome-dependent degradation of the phosphorylated FOXO3A³³ and the subsequent suppression of the BIM gene's transcription that is reliant on FOXO3A.³⁴ Furthermore, MCL-1 is stabilized and enhances the survival rate of tumor cells when ERK phosphorylates it on threonine-163 via the PEST domain. Many cancer types have increased MCL-1 expression, which is associated with both a poor prognosis and drug resistance.³⁵ The ERK signaling pathway is a key target for cancer therapy, with Raf inhibitors like Sorafenib being among the most effective treatments available.³⁶ A common feature of lung and colorectal cancers is EGFR gene mutation, which triggers the ERK pathway.^37,38 Unusual EGFR triggering is found in around 80% of lung cancer with non-small cell carcinoma patients.³⁹ Most EGFR mutations have an in-frame deletion in the tyrosine kinase domain, activating PI3K-Akt and Raf-MEK-ERK signaling pathways.⁴⁰ Gefitinib and erlotinib, EGFR inhibitors, help slow cell growth in non-small cell lung cancer.⁴¹ The EGFR-activated signaling pathways are being explored as potential targets for creating innovative therapeutics for lung cancer.^42,43

MAPK pathway role in Diabetes mellitus:

The same meals and substances that also increase ERK1/2 activation also enhance insulin secretion.^44,45 The activation of ERK1/2 requires glucose absorption and metabolism. sulfonylurea or K+ depolarization of beta cells as an antidiabetic medication activates ERK1/2, however not with the same kinetics as glucose.^45,46 Voltage-gated calcium channels play a decisive role in activating ERK when glucose concentration increases.^44,46,47 Glucagon-like peptide I (Glp1), those certain nutrients, and glucose are necessary for the phosphoprotein phosphatase calcineurin, which is dependent on calcium and calmodulin, to activate ERK1/2.^48,49 Within the normal physiological range, glucose concentrations induce the transcription of the insulin gene.^50,51 The insulin genetic factor enhancer's glucose-responsive regions are found close to the transcription start point. Several transcription factors, important in both beta cell formation and insulin gene transcription, have tissue-restricted expression. These transcription factors include Beta2, PDX-1, and MafA.^52,53 These tissue-specific factors bind to the glucose-sensitive areas of beta cells, activating the particular insulin gene expression that these cells show. It has been demonstrated that all three of these components undergo functional alterations brought on by phosphorylation, particularly DNA binding, and that they are all in vitro substrates of ERK1/2. Mutations in PDX-1 and Beta2 are linked to MODY type 4 and 6, respectively.⁵³ Elevated glucose concentrations for longer than 24 hours can block insulin gene transcription.^54,55 Chronic high blood sugar triggers C/EBP-β expression. C/EBP-β binds to the insulin gene promoter via ERK1/2, disrupting transcription factors and blocking insulin production. How ERK1/2 regulates this interaction remains unclear, but its phosphorylation likely contributes to insulin gene suppression in type II diabetes. Beta cells, due to high insulin output, are especially vulnerable to ER stress.⁵⁶ Beta cell apoptosis may be triggered by ER stress. Cell damage activates CHOP, a C/EBP-β homologous factor that, by unknown pathways, adds to ER stress. Reverse the translation block triggering the first ER stress response.^57,58 During ER stress, beta cell survival is prolonged by CHOP knockout.⁵⁹

CHOP transcription is suppressed by ERK1/2 activation. The insulin gene's MafA binding site is identical to the region present in the CHOP gene's promoter. When cells are subjected to physiologically normal glucose concentrations, MafA attaches itself to the CHOP promoter.⁶⁰ In reconstitution experiments, MafA binding reduces MafA binding to the CHOP gene and suppresses ERK1/2 activity, which in turn reduces CHOP promoter activity. The idea that MafA prevents beta cells from producing CHOP is in line with the finding that ERK1/2 activation inhibition increases the production of CHOP proteins. Therefore, ERK1/2 both favorably and negatively regulates genes essential for beta cell activity.

Conclusion: The review provides detailed insights into the pathogenic involvement of the MAPK pathway in cancer, PCOS, Alzheimer's disease, and diabetes mellitus, Different targets can be found for innovative treatment, such as ERK1/2 in PCOS, mutations in ras and B-raf within the erk pathway in cancer, and the function of JNK, P38, and ERK in Alzheimer's disease.

Abbreviations:

MAPK	Mitogen-Activated Protein Kinase
MAP2K	Mitogen-Activated Protein Kinase Kinase
MAP3K	Mitogen-Activated Protein Kinase Kinase Kinase
JNK	c-Jun N-terminal Kinase
ERK	Extracellular signal-Regulated Kinase
TNF-α	Tumor Necrosis Factor Alpha
IL-1 β	Interleukin 1 Beta
ASK1	Apoptosis Signal-Regulating Kinase 1
TAK1	Transforming Growth Factor Beta-Activated Kinase 1
MKK	Mitogen-Activated Protein Kinase Kinase
Raf	Rapidly Accelerated Fibrosarcoma
RTK	Receptor Tyrosine Kinase
MEK	MAPK/ERK Kinase
PKD	Polycystic Kidney Disease
cAMP	Cyclic Adenosine Monophosphate
EGFR	Epidermal Growth Factor Receptor
PI3K	Phosphoinositide 3-Kinase
Akt	Protein Kinase B
BIM	Bcl-2 Interacting Mediator of Cell Death
MCL-1	Myeloid Cell Leukemia Sequence 1
FOXO3A	Forkhead Box O3A
PEST	Proline, Glutamic Acid, Serine, and Threonine-rich domain
MODY	Maturity-Onset Diabetes of the Young
Glp1	Glucagon-like Peptide 1
PDX-1	Pancreatic and Duodenal Homeobox 1
MafA	Musculoaponeurotic Fibrosarcoma Oncogene Homolog A
C/EBP-β	CCAAT/Enhancer-Binding Protein Beta
CHOP	C/EBP Homologous Protein
LPS	Lipopolysaccharide
ROS	Reactive Oxygen Species
Ca2+	Calcium Ion

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Received on 13.09.2024 Revised on 16.01.2025

Accepted on 19.03.2025 Published on 01.10.2025

Available online from October 04, 2025

Research J. Pharmacy and Technology. 2025;18(10):5066-5070.

DOI: 10.52711/0974-360X.2025.00732

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