Exploring the Influence of c-Jun N terminal Kinase Scaffold Proteins on the Spatiotemporal Regulation of JNK Activation in Pancreatic Ductal Adenocarcinoma

Abstract

.c-Jun N terminal kinase (JNK) activation plays a significant role in dictating cell fate outcomes. Especially, in response to cellular stress inducers such as: Sodium Arsenide and Hydrogen peroxide(H2O2). Biochemically, the p38 and JNK-MAPK can activate the SAPK (Stress Activated Protein Kinase) pathways. This same stress granules can also reduce the SAPK apoptotic response. Where the RACK-1(Receptor for C kinase-I) functions as a binding agent to initiate the stress granule signaling pathway-2¹³. In normal human microenvironment, JNK isoforms have been found responsible for showcasing tumor suppressive characteristics. Similarly, the JNK and H-RAS (Harvey Rat Sarcoma Virus) can also initiate forward genetic screenings in mice with KRASG-12D allele and Pdx1-Cre transgene¹⁴. Normally, PDAC is an aggressive malignancy with a survival rate of only 13%. The inactivation of the drug, multi-drug resistance, cell death inhibition (apoptosis suppression), altering in the drug metabolism, epigenetic changing, changes in the drug targets can lead to the development of high resistance against Oxaliplatin ^(2,17). This aggressive form of malignancy mostly results in missense mutation, especially at the thermodynamically active sequences of the KRAS (Kirsten Rat Sarcoma Virus) such as C118S, G12A, G12D, G12V, and Q61H. However, our primary focus is G12D. The Oxaliplatin-led chemoresistance in both cell-autonomous and non-autonomous secretions of the 15d-PGJ2 prostaglandin have been proposed to faciliatate for the development of the PDAC ^(3–4). Similar to JNK, the WD Repeat Domain 62 (WDR-62) may also lead to the development of Pancreatic Ductal Adenocarcinoma (PDAC)¹. WDR-62 functions as a novel JNK (c-Jun N terminal kinase) binding protein, only been expressed in heat-sensitive circumstances and is a part of the mitogen-activated protein kinase pathway (MAPK). WDR-62 is a 175KDa-long protein that binds to the JNK and alters the MAPK signaling cascade. As a novel scaffold protein WDR-62 can bind with other scaffolds such as JIP-1, JIP-2, and JIP-3 to control the overexpression of stress granules in PDAC¹. The WDR-62 inhibits the AP-1 transcription through the recruitment of the JNK to a non-nuclear compartment¹. Moreover, JNK and WDR-62 can regulate the dynamic interplay between the stress granules, thereby mediating the mRNA-generated stresses¹. In general, the Stress granules and 15d-PGJ2 prostaglandin have been suggested to regulate the regional and time-specific JNK activations.WDR-62 leads to phosphorylation, activating the classical, non-classical, and overexpression of the stress granules and the expression of TIA (Tumor Induced Angiogenesis) and TTP (Thrombotic Thrombocytopenic Purpura). We hypothesize the knockdown of the WDR-62 by Si-RNA, can lead to the suppression of Oxaliplatin resistant WDR-62 gene-initiated DNA repairing system and the regulation of the normal cell signaling process of the MAPK, cell proliferation, apoptosis and mRNA homeostasis in PDAC.