Harnessing RKIP to Combat Heart Disease and Cancer

Abstract

Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity.

The Role of RKIP in the Regulation of EMT in the Tumor Microenvironment

“…In instances of tumors where RKIP is overexpressed, such as in multiple myeloma, the mutated form of serine 153 phosphorylated RKIP is the prominent form present, unable to inactivate the ERK pathway since it lacks the ability to interact with RAF1 [ 164 ]. In cancer, RAF1/MEK/ERK signaling is often lacking normal regulation through RKIP, since this signaling pathway controls mechanisms of cell proliferation, differentiation, and migration [ 165 ]. As discussed previously, the serine 153 phosphorylated RKIP loses its ability to interact with RAF1 and regulate the ERK pathway, allowing cancer cells to utilize the cells’ own mechanisms of proliferation and migration, and similarly, a lack of RKIP also allows the ERK signaling pathway to remain active and deregulated.…”

Cross-Talks between Raf Kinase Inhibitor Protein and Programmed Cell Death Ligand 1 Expressions in Cancer: Role in Immune Evasion and Therapeutic Implications

“…Upon phosphorylation at S153, a strong negative charge is induced and enables the nearby serine to compete with the negatively charged residues in the neighboring salt bridge. This competition results in the phosphorylated serine 'stealing' the positively charged lysine and forming a new salt bridge [57,63]. This newly established salt bridge induces the functional alteration in RKIP as previously described.…”

“…More than a decade later, Yeung et al discovered a breakthrough in the function of the protein, revealing its ability to inhibit Raf-1 in the mitogen-activated protein kinase (MAPK) pathway, earning its RKIP name [25]. Since then, researchers have elucidated RKIP's role in many signaling cascades beyond MAPK [54][55][56][57], along with a growing number of studies examining the loss of RKIP expression in many types of cancer [29,55,58].…”

Raf kinase inhibitor protein combined with phosphorylated extracellular signal-regulated kinase offers valuable prognosis in gastrointestinal stromal tumor

“…ERK and MEK proteins are two core proteins in the Raf1-MEK-ERK pathway, which are downstream targets activated by abnormal C-kit and PDGFR-α genes closely related to GIST. ERK protein is associated with various diseases[ 10 ] such as tumors, heart failure, developmental disorders, and autoimmune diseases[ 11 - 13 ]. RKIP protein is a natural inhibitor of Raf-1 protein and is widely present in living organisms.…”