Spatial regulation of ARAF controls the MST2-Hippo pathway

Abstract

The RAF-MAPK signaling pathway regulates several very diverse cellular processes such as proliferation, differentiation, apoptosis, and transformation. While the canonical function of RAF kinases within the MAPK pathway is the activation of MEK, our group could demonstrate an important crosstalk between RAF signaling and the pro-apoptotic mammalian sterile 20-like kinase (MST2) tumor suppressor pathway in several cancer entities, including head and neck, colon, and breast. Here, the RAF kinases CRAF and ARAF sequester and inhibit the pro-apoptotic kinase MST2 independently of their own kinase activity. In our recent study, we showed that the ARAF-MST2 complex is regulated by subcellular compartmentalization during epithelial differentiation. Proliferating cells of the basal cell layer in squamous epithelia and tumor cells express ARAF at the mitochondria thus allowing for efficient sequestration of MST2. In contrast, non-malignant squamous epithelia have ARAF localized at the plasma membrane, where the control of MST2-mediated apoptosis is compromised. This re-distribution is regulated by the scaffold protein kinase suppressor of Ras 2 (KSR2). Here, we summarize how spatial and temporal regulation of RAF signaling complexes affect cellular signaling and functions.

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

“…Similar to CRAF, ARAF also binds and sequesters MST2 independent of its kinase activity [125]. ARAF interaction with MST2 is dependent on the presence of full-length splicing product controlled by hnRNP H [126].…”

WW Domain-Containing Proteins YAP and TAZ in the Hippo Pathway as Key Regulators in Stemness Maintenance, Tissue Homeostasis, and Tumorigenesis

“…In this process, PD-L1 expression is suppressed by the upstream kinases MST1/2 and LATS1/2 of the Hippo pathway, while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines. Critically, TAZ-induced PD-L1 upregulation in human cancer cells is sufficient to inhibit T cell function (181). Further, in vitro studies indicate that cultured breast cancer cells exhibit high YAP/TAZ activity and confer drug-resistance to many routinely used chemotherapeutic drugs, such as taxol, 5-fluorouracil, and doxorubicin (182–184).…”

Oncogenic Ras Isoforms Signaling Specificity at the Membrane

“…The mobile nature of Ras molecules at the membrane, the fleeting residence times, and the absence of clear dominant states – at least in the time scales and PM composition that current molecular dynamics simulations of these huge systems can afford – question the efficacy of targeting preferred membrane interaction states. By contrast, productive cell-specific signaling pathways and cross-talk (23, 146, 147) appear more promising candidates; however, ferreting the complexes and poses to drug presents an even more daunting challenge. Lower drug toxicity calls for specificity; yet, working out the key factors that differentiate among isoforms is demanding.…”

“…Ras isoforms signal effectively when anchored and enriched at the plasma membrane (PM) (16–21). Signaling pathways include mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K), Ras-Ral guanine nucleotide dissociation stimulator (RalGDS), phospholipase C ε (PLCε), Cdc42/Rac, Ras association domain family 5 (RASSF5, also known as NORE1A) mediating mammalian sterile 20-like kinase 1/2 (MST1/2) Hippo pathway (albeit with limited direct experimental data supporting RASSF5 repressing Yes-associated protein 1 (YAP1) activity (22)), as well as the emerging pathway cross-talk (23).…”