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Mechanisms of Wnt signaling in early vertebrate development

Non-transcriptional WNT/STOP signaling

Figure 1: Post-transcriptional Wnt signaling regulates sperm maturation. Wnt inhibits Gsk3 to affect i) inhibition of protein poly-ubiquitination to maintain protein homeostasis (Wnt/STOP signaling); ii) promoting septin 4 polymerization, thereby maintaining sperm structural integrity; iii) inhibition of protein phosphatase 1 to unlock sperm motility (Koch et al., 2015).

We previously showed that LRP6 phosphorylation is under cell cycle control, peaking in G2/M (Davidson et al., 2009). This is because the G2/M Cyclin Y (CCNY) – CDK14 complex phosphorylates LRP6, and thereby primes it for Wnt-dependent CK1 phosphorylation. It is curious that Wnt signaling should peak during transcriptionally silent mitosis, when its major effects are thought to require β-catenin-dependent gene transcription. As a solution to this conundrum, we have discovered a novel Wnt pathway, termed: Wnt-dependent stabilization of proteins (Wnt/STOP). This pathway is independent of β-catenin, peaks during mitosis and stabilizes proteins that are essential for various biological functions such as cell division (Acebron et al., 2014).

Recently, key evidence demonstrating the in vivo relevance of this new transcription-independent Wnt pathway, was obtained in mice. We generated Ccnyl1 knockout mice and discovered they are sterile due to severe sperm structural and motility defects. Analysis of these mice showed that Wnts act as an epididymal sperm maturation signal. Wnt signaling contributes to the terminal differentiation of spermatozoa through at least three distinct mechanisms that trifurcate at the level of GSK3 (Fig. 1). Thus, a multifaceted set of Wnt functions in sperm development is implemented post-transcriptionally through mechanisms that maybe relevant to other tissues as well (Koch et al., 2015). Our current efforts aim at identifying novel WNT/STOP target proteins and to study the physiological processes where this pathway is involved.

Role of DEAD box helicases in kinase regulation during Wnt signaling

We have previously identified the DEAD-box RNA helicase DDX3 as a novel member of the Wnt-β-catenin network in embryonic development, where it acts as a regulator of Casein kinase 1 epsilon (CK1ε; Cruciat et al. 2013). Our unpublished work indicates that other members of the 37 DEAD-box RNA helicases can also function as CK1 kinase regulators in Wnt signaling, and that this extends beyond CK1ε. For our future work, we will validate our findings and seek to establish that DEAD box helicases have a generic function in regulating diverse protein kinases in the context of Wnt signaling.

Characterization of novel components of the Wnt pathway

Figure 2: Parkinson associated GPR37 is an LRP6 chaperone. The large cysteine-rich domains of LRP6 require assisted folding by GPR37. This transmembrane protein protects LRP6 from ER-associated degradation (ERAD) (Berger et al., 2017). Cover picture of EMBO Reports.

One continuing line of research in the lab is to identify novel Wnt pathway regulators, study their physiological significance, and elucidate their biochemical mode of action. In the past period, we have characterized two new components, GPR37 and ANGPTL4. Both proteins act at the receptor level and interact with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6).

Recently, we found that Parkinson-associated receptor GPR37 functions in the maturation of the N-terminal bulky ß-propellers of the Wnt co-receptor LRP6. GPR37 is required for Wnt/β-catenin signaling and protects LRP6 from ER associated degradation via CHIP (carboxyl terminus of Hsc70-interacting protein) and the ATPase VCP. GPR37 is highly expressed in neural progenitor cells (NPCs) where it is required for Wnt-dependent neurogenesis. Thus, GPR37 is a new transmembrane chaperone for LRP6, which is crucial for cellular protein quality control during Wnt signaling (Fig. 2) (Berger et al., 2017).

Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein, which is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. In a siRNA screen we identified ANGPTL4 as a Wnt signaling antagonist, which binds to syndecans and forms a ternary complex with LRP6. This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation of Wnt/β-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function of ANGPTL4 invites re-interpretation of its diverse physiological effects in light of Wnt signaling and may open novel therapeutic avenues for major human diseases (Kirsch et al., 2017).

We are continuing to identify and characterize other new Wnt pathway components.

Cancer cell specific inhibition of Wnt/β-catenin signaling

Use of the diabetes type II drug Metformin is associated with a moderately lower risk of cancer incidence in numerous tumor entities. By studying the molecular changes associated with the tumor-suppressive action of Metformin, we discovered that the oncogene SOX4, which is upregulated in solid tumors and associated with poor prognosis, was induced by Wnt/β-catenin signaling and blocked by Metformin. Wnt signaling inhibition by Metformin was surprisingly specific for cancer cells. By studying the underlying mechanisms, we identified Metformin and other Mitochondrial Complex I (MCI) inhibitors as inducers of intracellular acidification in cancer cells. We demonstrated that acidification triggers the unfolded protein response to induce the global transcriptional repressor DDIT3, which is known to block Wnt signaling. Based on these findings, we combined MCI inhibitors with H+ Ionophores, to deliberately promote intracellular hyper-acidification and ATP depletion in cancer cells. This treatment lowered intracellular pH in vitro and in a mouse xenograft tumor model, depleted cellular ATP, blocked Wnt signaling, downregulated SOX4, and strongly decreased the stemness and viability of lung cancer cells. Importantly, the inhibition of Wnt signaling occurred downstream of β-catenin, suggesting applications in treatment of cancers caused by APC and β-catenin mutations (Melnik et al., 2018). As a follow up to these important findings, we aim to develop novel approaches for the treatment of Wnt–addicted tumors using small molecules.

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