Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

Abstract

Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases.

Imatinib Treatment Causes Substantial Transcriptional Changes in Adult Schistosoma mansoni In Vitro Exhibiting Pleiotropic Effects

“…Among these were paramyosin (Smp_129550) and titin (Smp_105020), both proteins involved in muscle activity [73], [74], and a ribosomal protein S6 kinase (Smp_017900) due to its potential role as a MAPK-activated PK in signalling processes controlling diverse processes including survival [75], [76]. Furthermore, HSP70 (Smp_106930) was chosen due to its known roles in stress response and signal transduction processes, but also as egg-shell component in schistosomes [77]–[79].…”

MK5: A novel regulator of cardiac fibroblast function?

“…There are also protein kinases downstream of and activated by MAPKs. These protein kinases, the MAPK‐activated protein kinases, or MKs, include MK1/p90 ribosomal protein S6 kinases (rsk1–4), mitogen‐ and stress‐activated kinases (MSK1/2), MAPK‐interacting kinases (MNK1/2), MK2, MK3, and MK5/p38‐regulated/activated kinase .…”

Comparative Molecular Dynamics Simulations of Mitogen-Activated Protein Kinase-Activated Protein Kinase 5

“…Atypical MAPKs lack this motif, and are not organized in the classical consecutive phosphorylation cascade of three Ser/Thr protein kinases. Atypical MAPKs comprise ERK3/4, ERK7/8 and the Nemo-like kinases (NLK) [2]. …”

“…However, MK5 is different from the others since MK5 is phosphorylated and activated both by conventional (p38) and atypical (ERK3 and ERK4) MAPKs (Figure 1) [1,2,5]. ERK3 and ERK4 have been suggested to catalyse phosphorylation at Thr182 and activate MK5 [6,7].…”

“…These studies have shown that MK5 may be involved in a wide range of biological processes including control of the cytoskeletal architecture by F-actin remodelling [12,23–26], tumour growth and progression by stimulating angiogenesis [27], tumour suppression by Myc downregulation or antagonizing the JNK pathway [28,29], or interfering with ERK3-mediated cell cycle control, and B-cell development by activating Rag transcription via Foxol [18,30–32]. Further, MK5 was also suggested to be involved in the inflammatory response as a consequence of microbial infection [33] and heart function [2]. Animal studies have also suggested a role of MK5 in neurological processes controlling anxiety and locomotion [34,35].…”