Navigating the ERK1/2 MAPK Cascade

Abstract

The RAS-ERK pathway is a fundamental signaling cascade crucial for many biological processes including proliferation, cell cycle control, growth, and survival; common across all cell types. Notably, ERK1/2 are implicated in specific processes in a context-dependent manner as in stem cells and pancreatic β-cells. Alterations in the different components of this cascade result in dysregulation of the effector kinases ERK1/2 which communicate with hundreds of substrates. Aberrant activation of the pathway contributes to a range of disorders, including cancer. This review provides an overview of the structure, activation, regulation, and mutational frequency of the different tiers of the cascade; with a particular focus on ERK1/2. We highlight the importance of scaffold proteins that contribute to kinase localization and coordinate interaction dynamics of the kinases with substrates, activators, and inhibitors. Additionally, we explore innovative therapeutic approaches emphasizing promising avenues in this field.

miR-483-5p orchestrates the initiation of protein synthesis by facilitating the decrease in phosphorylated Ser209eIF4E and 4E-BP1 levels

“…In pathological conditions, such as those associated with tumor-promoting factors, the ERK pathway is also activated. While the individual effects of the cascading activation signals are extensively studied for each kinase 41 , 42 , the well-established function of the ERK1/MKNK1 axis is to phosphorylate the mRNA cap-binding protein eIF4E 15 , 22 , 43 , 44 .…”

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

“…Thus, a MAPK kinase kinase (MAP3K) phosphorylates and activates a MAPK kinase (MKK) which phosphorylates the MAPK. For the ERK1/2 cascade [10,11], the core cascade is initiated by RAF family kinases of which there are 3 isoforms (RAF1, BRAF and ARAF). These kinases phosphorylate and activate MEK1 and MEK2 (also known as MKK1 and MKK2).…”

“…Thus, MEK1/2 phosphorylate ERK1/2 on both Thr and Tyr residues of a TEY motif to induce full activation. The regulation of each component of the cascade is complex as reviewed in [10,11], with activating and inhibitory phosphorylations affecting protein kinase activities directly, in addition to phosphorylations that promote or disrupt protein-protein interactions. The latter may facilitate or prevent activation, or target the enzymes to different compartments of the cell.…”

“…The ERK1/2 cascade is activated by a wide range of stimuli including peptide growth factors such as epidermal growth factor (EGF) that bind to and activate receptor tyrosine kinases (RTKs). Activated RTKs recruit signalling proteins to the receptor, including adapter proteins such as GRB2 that bring other proteins to the complex like SOS, an exchange factor for RAS small G proteins (HRAS, KRAS and NRAS) [11,13]. RAS acts as a molecular switch for the system: it is inactive when bound to GDP and exchange of GDP for GTP, catalysed by exchange factors such as SOS, results in a conformational change and activation.…”

“…Because of the increasing incidence of cancer therapy-related cardiovascular risk, there are already many reviews on the topic in general. Here, we focus on the drugs which target the pivotal signalling cascade that drives cell division, the prototypic mitogen-activated protein kinases (MAPKs) now known as the extracellular signalregulated kinases 1/2 (ERK1/2) [10,11]. As explained below, each component of the cascade is a target for anti-cancer therapies.…”