Disruption of Wnt Planar Cell Polarity Signaling by Aberrant Accumulation of the MetAP-2 Substrate Rab37

Sundberg, Thomas B.; Darricarrère, Nicole; Cirone, Pasquale; Li, Xia; McDonald, Lucy; Xue, Mei; Westlake, Christopher J.; Slusarski, Diane C.; Beynon, Robert J.; Crews, Craig M.

doi:10.1016/j.chembiol.2011.07.020

Cited by 27 publications

(25 citation statements)

References 47 publications

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“…Therapeutic strategies such as DNA demethylation of hRAB37 gene (ref. 14) and increased stability of hRAB37 protein 41 could facilitate the development of cancer therapy.…”

Section: Wt-timp1kd +Timp1mentioning

confidence: 99%

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

et al. 2014

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Rab small GTPases are master regulators of membrane trafficking and guide vesicle targeting. Recent publications show that Rab-controlled trafficking pathways are altered during tumorigenesis. However, whether any of the Rabs plays a metastasis suppressor role is least explored. Here we address the metastasis suppressive function of human Rab37 (hRAB37) using secretomics, cell, animal and clinical analyses. We show that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted glycoprotein that inhibits extracellular matrix turnover, is a novel cargo of hRAB37. hRAB37 regulates the exocytosis of TIMP1 in a nucleotide-dependent manner to inactivate matrix metalloproteinase 9 (MMP9) migration axis in vitro and in vivo. Dysfunction of hRAB37 or TIMP1 abrogates metastasis suppression. Lung cancer patients with metastasis and poor survival show low hRAB37 protein expression coinciding with low TIMP1 in tumours. Our findings identify hRAB37 as a novel metastasis suppressor Rab that functions through the TIMP1-MMP9 pathway and has significant prognostic power.

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“…Therapeutic strategies such as DNA demethylation of hRAB37 gene (ref. 14) and increased stability of hRAB37 protein 41 could facilitate the development of cancer therapy.…”

Section: Wt-timp1kd +Timp1mentioning

confidence: 99%

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

et al. 2014

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“…Naturally occurring and manufactured compounds that specifically inhibit the Wnt/PCP pathway have been identified [350], opening the door for development of new agents that can selectively inhibit or activate this pathway via similar molecular mechanisms [351]. In closing, as each of the Wnt pathways - even the most divergent pathways discussed in the preceding sections - is biochemically characterized, they provide promising targets for rational drug exploration and development in psychiatry with a clear path forward through the use of animal and hiPSC models as prescribed above.…”

Section: Concluding Remarks: Therapeutic Considerationsmentioning

confidence: 99%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

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“…ICG001 and TNP470 both disrupted the process (Supplemental Figure 2A). ICG001 interferes with canonical Wnt signaling by blocking the interaction between β-catenin and CREB binding protein (CBP) (21), while TNP470 inhibits the noncanonical planar cell polarity pathway (22). To test whether ICG001 and TNP470 interfered with mISL1-CPC spheroid formation by inducing cell death, we next plated ISL1-CPCs on fibronectin-coated plates and treated them with these inhibitors for 24 hours.…”

Section: Resultsmentioning

confidence: 99%

ISL1 cardiovascular progenitor cells for cardiac repair after myocardial infarction

et al. 2016

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Cardiovascular progenitor cells (CPCs) expressing the ISL1-LIM–homeodomain transcription factor contribute developmentally to cardiomyocytes in all 4 chambers of the heart. Here, we show that ISL1-CPCs can be applied to myocardial regeneration following injury. We used a rapid 3D methylcellulose approach to form murine and human ISL1-CPC spheroids that engrafted after myocardial infarction in murine hearts, where they differentiated into cardiomyocytes and endothelial cells, integrating into the myocardium and forming new blood vessels. ISL1-CPC spheroid–treated mice exhibited reduced infarct area and increased blood vessel formation compared with control animals. Moreover, left ventricular (LV) contractile function was significantly better in mice transplanted with ISL1-CPCs 4 weeks after injury than that in control animals. These results provide proof-of-concept of a cardiac repair strategy employing ISL1-CPCs that, based on our previous lineage-tracing studies, are committed to forming heart tissue, in combination with a robust methylcellulose spheroid–based delivery approach.

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Disruption of Wnt Planar Cell Polarity Signaling by Aberrant Accumulation of the MetAP-2 Substrate Rab37

Cited by 27 publications

References 47 publications

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

ISL1 cardiovascular progenitor cells for cardiac repair after myocardial infarction

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