<i>dEHBP1</i> regulates Scabrous secretion during Notch mediated lateral inhibition

Γιαγτζόγλου, Νικόλαος; Li, Tongchao; Yamamoto, Shinya; Bellen, Hugo J.

doi:10.1242/jcs.126292

Cited by 11 publications

(10 citation statements)

References 99 publications

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“…This conclusion is also supported by earlier indirect data suggesting a role of EHBP1 in invasive growth (21)(22)(23). More recent data show that drosophila EHBP1 regulates aspects of Notch signaling (37), and that Notch may play a role in metastatic prostate cancer (38). Taken together with our data they suggest that further studies of EHBP1 as an inhibitor of invasiveness is warranted, and in particular as EHBP1 is a target for non-toxic drugs.…”

Section: Discussionsupporting

confidence: 91%

Atorvastatin prevents ATP-driven invasiveness via P2X7 and EHBP1 signaling in PTEN-expressing prostate cancer cells

Ghalali¹,

Wiklund

Zheng³

et al. 2014

Carcinogenesis

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Epidemiological studies indicate that statins, cholesterol-lowering drugs, prevent aggressive prostate cancer and other types of cancer. Employing essentially non-prostate cell lines, we previously showed that statins rapidly downregulate nuclear levels of phosphorylated Akt via P2X7, a purinergic receptor recently implicated in invasive growth. Here, we present studies on phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-positive prostatic cells. We document an involvement of EH domain-binding protein 1 (EHBP1), previously associated with aggressive prostate cancer and insulin-stimulated trafficking and cell migration, in P2X7 signaling. We also show that EHBP1 is essential for an anti-invasive effect of atorvastatin. Furthermore, EHBP1 interacted with P-Rex1, a guanine nucleotide exchange factor previously implicated in invasive growth. Mevalonate did not prevent this anti-invasive effect of atorvastatin. These data indicate that atorvastatin modulates invasiveness via P2X7, EHBP1 and P-Rex1. Interestingly, the interaction between EHBP1 and P-Rex1 was not induced by extracellular adenosine triphosphate (ATP), the endogenous P2X7 ligand, and statins counteracted invasiveness stimulated by extracellular ATP. In support of these experimental data, a population-based genetic analysis showed that a loss of function allele in the P2X7 gene (rs3751143) associated with non-aggressive cancer, and the common allele with aggressive cancer. Our data indicate a novel signaling pathway that inhibits invasiveness and that is druggable. Statins may reduce the risk of aggressive prostate cancer via P2X7 and by counteracting invasive effects of extracellular ATP.

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Section: Discussionsupporting

confidence: 91%

Atorvastatin prevents ATP-driven invasiveness via P2X7 and EHBP1 signaling in PTEN-expressing prostate cancer cells

Ghalali¹,

Wiklund

Zheng³

et al. 2014

Carcinogenesis

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“…In C. elegans , EHBP1 depletion leads to an endocytic recycling defect in the intestine and in nonpolarized germline cells and the phenotype was recapitulated upon Rab8/10 deletion 8 . Drosophila EHBP1 has been shown to play an essential role in eye development by regulating the exocytosis of Scabrous, a positive regulator of Notch signaling 9 . Notch signaling has been implicated in metastatic prostate cancer, and a genome-wide SNP association study shows that EHBP1 is associated with aggressive disease 10 – 13 .…”

Section: Introductionmentioning

confidence: 99%

The mechanism of activation of the actin binding protein EHBP1 by Rab8 family members

et al. 2020

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EHBP1 is an adaptor protein that regulates vesicular trafficking by recruiting Rab8 family members and Eps15-homology domain-containing proteins 1/2 (EHD1/2). It also links endosomes to the actin cytoskeleton. However, the underlying molecular mechanism of activation of EHBP1 actin-binding activity is unclear. Here, we show that both termini of EHBP1 have membrane targeting potential. EHBP1 associates with PI(3)P, PI(5)P, and phosphatidylserine via its N-terminal C2 domain. We show that in the absence of Rab8 family members, the C-terminal bivalent Mical/EHBP Rab binding (bMERB) domain forms an intramolecular complex with its central calponin homology (CH) domain and auto-inhibits actin binding. Rab8 binding to the bMERB domain relieves this inhibition. We have analyzed the CH:bMERB auto-inhibited complex and the active bMERB:Rab8 complex biochemically and structurally. Together with structure-based mutational studies, this explains how binding of Rab8 frees the CH domain and allows it to interact with the actin cytoskeleton, leading to membrane tubulation.

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“…ehbp-1 mutants or RNAi also produce phenotypes in non-polarized cells very similar to simultaneous loss of RAB-10 and its closest paralog RAB-8, including variable larval arrest, and fully penetrant adult sterility due to a failure in germline membrane transport and oocyte growth [ 15 ]. In Drosophila dEHBP1 has also been reported to act with Rab11 [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

RAB-10 Promotes EHBP-1 Bridging of Filamentous Actin and Tubular Recycling Endosomes

et al. 2016

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EHBP-1 (Ehbp1) is a conserved regulator of endocytic recycling, acting as an effector of small GTPases including RAB-10 (Rab10). Here we present evidence that EHBP-1 associates with tubular endosomal phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] enriched membranes through an N-terminal C2-like (NT-C2) domain, and define residues within the NT-C2 domain that mediate membrane interaction. Furthermore, our results indicate that the EHBP-1 central calponin homology (CH) domain binds to actin microfilaments in a reaction that is stimulated by RAB-10(GTP). Loss of any aspect of this RAB-10/EHBP-1 system in the C. elegans intestinal epithelium leads to retention of basolateral recycling cargo in endosomes that have lost their normal tubular endosomal network (TEN) organization. We propose a mechanism whereby RAB-10 promotes the ability of endosome-bound EHBP-1 to also bind to the actin cytoskeleton, thereby promoting endosomal tubulation.

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dEHBP1 regulates Scabrous secretion during Notch mediated lateral inhibition

Cited by 11 publications

References 99 publications

Atorvastatin prevents ATP-driven invasiveness via P2X7 and EHBP1 signaling in PTEN-expressing prostate cancer cells

Atorvastatin prevents ATP-driven invasiveness via P2X7 and EHBP1 signaling in PTEN-expressing prostate cancer cells

The mechanism of activation of the actin binding protein EHBP1 by Rab8 family members

RAB-10 Promotes EHBP-1 Bridging of Filamentous Actin and Tubular Recycling Endosomes

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