HGF-induced migration depends on the PI(3,4,5)P3-binding microexon-spliced variant of the Arf6 exchange factor cytohesin-1

Ratcliffe, Colin D.H.; Siddiqui, Nadeem; Coelho, Paula P.; Laterreur, Nancy; Cookey, Tumini N.; Sonenberg, Nahum; Park, Morag

doi:10.1083/jcb.201804106

Cited by 29 publications

(22 citation statements)

References 65 publications

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“…Met recycling was not perturbed in IQSEC1-depleted cells, suggesting another ARFGEF may promote this function. The PI(4,5)P2/PIP3dependent Cytohesin-1 ARFGEF is one candidate for this, as we note upregulation in PC3, and it is required downstream of Met for invasive activity in other cells 63 .…”

Section: Discussionmentioning

confidence: 67%

Spatial enrichment of phosphoinositide metabolism is a molecular switch to promote metastasis

Nacke

Sandilands

Nikolatou

et al. 2019

Preprint

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The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. We developed 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that select IQSEC1 variants, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by spatially restricting cortical phosphoinositide metabolism. All IQSEC1 variants activate ARF5-and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants restrict cortical PI(3,4,5)P3 production to discrete domains, resulting in formation of invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion and metastasis in vitro and in vivo. IQSEC1-ARF expression predicts long-term outcome in prostate cancer patients. Spatial restriction of phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch represents a therapeutic vulnerability to stop metastasis. Highlights• Spatial restriction of PI(3,4,5)P3 is a molecular switch to promote invasion.• IQSEC1 is a GEF for ARF5/6, promoting PIP5K-dependent PI(3,4,5)P3 production downstream of the HGF receptor Met.• Pro-invasive IQSEC1 variants restrict cortical PI(3,4,5)P3 production to select cortical subdomains that convert into invasive protrusions.• IQSEC1 inhibition attenuates in vitro invasion and metastasis in vivo.• IQSEC1 module expression predicts disease-free survival in prostate cancer.

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Section: Discussionmentioning

confidence: 67%

Spatial enrichment of phosphoinositide metabolism is a molecular switch to promote metastasis

Nacke

Sandilands

Nikolatou

et al. 2019

Preprint

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“…Arl4c recruits all members of the cytohesin family to the plasma membrane by binding with the pleckstrin homology domain present on cytohesins. At the plasma membrane, cytohesins can recruit and activate Arf6 by promoting GDP/GTP exchange through the Sec7 domain (Hofmann et al, 2007; Ratcliffe et al, 2019). Importantly, in Schwann cells, Fyn regulates Cyth-1 GEF activity towards Arf6 by phosphorylating its Tyr 382 , a mechanism that may be present in other cytohesins (Yamauchi et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

CRL5-dependent regulation of Arl4c and Arf6 controls hippocampal morphogenesis

Han

Hino

Reyes

et al. 2020

Preprint

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SummaryThe small GTPase Arl4c participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The Arl4c signaling cascade starts by the recruitment of the Arf-GEF cytohesins to the plasma membrane, which in turn engage the small GTPase Arf6. In the nervous system, Arf6 regulates dendrite outgrowth in vitro and neuronal migration in the developing cortex. However, the role of Arl4c-cytohesin-Arf6 signaling during brain development and particularly during hippocampal development remain elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/Rbx2 (CRL5) controls the stability of Arl4c and its signaling effectors to regulate hippocampal morphogenesis. Rbx2 knock out causes hippocampal pyramidal neuron mislocalization and formation of multiple apical dendrites. The same phenotypes were observed when Cullin 5 was knocked down in pyramidal neurons by in utero electroporation. We used quantitative mass spectrometry to show that Arl4c, Cytohesin-1/3, and Arf6 accumulate in the telencephalon when Rbx2 is absent. Arl4c expression is post-transcriptionally regulated, with a peak in expression at early postnatal stages, and is localized at the plasma membrane and on intracellular vesicles in hippocampal pyramidal neurons. Furthermore, we show that depletion of Arl4c rescues the phenotypes caused by Cullin 5 knock down in the hippocampus, whereas depletion of Arf6 exacerbates over-migration. Finally, we show that Arl4c and Arf6 are necessary for the dendritic outgrowth of pyramidal neurons to the most superficial strata of the hippocampus. Overall, we identified CRL5 as a key regulator of hippocampal development and uncovered Arl4c and Arf6 as novel CRL5-regulated signaling effectors that control pyramidal neuron migration and dendritogenesis.

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“…Like many genes, human HGF and mouse Hgf encode multiple alternative transcripts, most of which have not been well studied . The importance of identifying and then studying the function of each alternative transcript of a gene was recently highlighted when an alternatively spliced microexon in cytohesin 1 ( CYTH1 ), a gene encoding a guanidine exchange factor, was shown to be necessary for spatially restricting HGF‐MET signaling …”

Section: Receptors Relevant To Auditory Systemmentioning

confidence: 99%

“…70 The importance of identifying and then studying the function of each alternative transcript of a gene was recently highlighted when an alternatively spliced microexon in cytohesin 1 (CYTH1), a gene encoding a guanidine exchange factor, was shown to be necessary for spatially restricting HGF-MET signaling. 71 In 40 large families from Pakistan segregating deafness, the phenotype was linked to markers for the DFNB39 locus on chromosome 7. Homozygosity was detected for either a non-coding, evolutionarily conserved three base pair deletion or an overlapping 10 base pair deletion in the 3 0 UTR of a short alternative splice isoform of HGF of unknown function.…”

Section: Hearing Requires Hgf and Met Signalingmentioning

confidence: 99%

Growth factor and receptor malfunctions associated with human genetic deafness

Naz

Friedman

2019

Clinical Genetics

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A variety of different signaling pathways are necessary for development and maintenance of the human auditory system. Normal hearing allows for the detection of soft sounds within the frequency range of 20 to 20 000 Hz, but more importantly to perceive the human voice frequency band of 250 to 6000 Hz. Loss of hearing is common, and is a clinically heterogeneous disorder that can be caused by environmental factors such as exposure to loud noise, infections and ototoxic drugs. In addition, variants of hundreds of genes have been reported to disrupt processes required for hearing. Noncoding regulatory variants and variants of additional genes necessary for hearing remain to be discovered as many individuals with inherited deafness are without a genetic diagnosis, despite the advent of whole exome sequencing. Here, we discuss in detail some of these deafnesscausing variants of genes encoding a ligand or its receptor. Spotlighted in this review are three growth factor-receptor-pairs EDN3/EDNRB, HGF/MET and JAG/NOTCH, which individually are necessary for normal hearing. We also offer our perspective on unanswered questions, future challenges and potential opportunities for treatments emerging from molecular genetic and mechanistic studies of deafness due to these causes. K E Y W O R D SEDN3, EDNRB, hearing, HGF, inner ear defects, JAG, MET, NOTCH

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HGF-induced migration depends on the PI(3,4,5)P3-binding microexon-spliced variant of the Arf6 exchange factor cytohesin-1

Cited by 29 publications

References 65 publications

Spatial enrichment of phosphoinositide metabolism is a molecular switch to promote metastasis

Spatial enrichment of phosphoinositide metabolism is a molecular switch to promote metastasis

CRL5-dependent regulation of Arl4c and Arf6 controls hippocampal morphogenesis

Growth factor and receptor malfunctions associated with human genetic deafness

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