Transgenic overexpression of the secreted, extracellular EGF-CUB domain-containing protein SCUBE3 induces cardiac hypertrophy in mice

Yang, Hong-Chang; Cheng, Ching Feng; Djoko, Bambang; Lian, Wei; Tu, Cheng Fen; Tsai, Ming Tzu; Chen, Yen Hui; Chen, Chien‐Chang; Cheng, Chien Jui; Yang, Ruey Bing

doi:10.1016/j.cardiores.2007.03.014

Cited by 27 publications

(30 citation statements)

References 34 publications

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“…Indeed, biochemical and molecular studies have revealed physical interactions between Scube3 CUB domains and TGF-b1 (Yang et al, 2007), and have identified permissive roles of fulllength Scube1 on BMP2 activation, possibly through the recruitment of as-yet-unidentified proteases (Tu et al, 2008). Consistent with the latter, the deletion of the Scube1 C-terminal cysteine motif and the CUB domain by targeted disruption in the mouse results in defects in brain patterning that resemble those in mice lacking the BMP antagonist Noggin (McMahon et al, 1998;Tu et al, 2008).…”

Section: Discussionmentioning

confidence: 85%

Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells

Jakobs

Exner

Schürmann

et al. 2014

Journal of Cell Science

112

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All morphogens of the Hedgehog (Hh) family are synthesized as dual-lipidated proteins, which results in their firm attachment to the surface of the cell in which they were produced. Thus, Hh release into the extracellular space requires accessory protein activities. We suggested previously that the proteolytic removal of N-and Cterminal lipidated peptides (shedding) could be one such activity. More recently, the secreted glycoprotein Scube2 (signal peptide, cubulin domain, epidermal-growth-factor-like protein 2) was also implicated in the release of Shh from the cell membrane. This activity strictly depended on the CUB domains of Scube2, which derive their name from the complement serine proteases and from bone morphogenetic protein-1/tolloid metalloproteinases (C1r/C1s, Uegf and Bmp1). CUB domains function as regulators of proteolytic activity in these proteins. This suggested that sheddases and Scube2 might cooperate in Shh release. Here, we confirm that sheddases and Scube2 act cooperatively to increase the pool of soluble bioactive Shh, and that Scube2-dependent morphogen release is unequivocally linked to the proteolytic processing of lipidated Shh termini, resulting in truncated soluble Shh. Thus, Scube2 proteins act as protease enhancers in this setting, revealing newly identified Scube2 functions in Hh signaling regulation.

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Section: Discussionmentioning

confidence: 85%

Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells

Jakobs

Exner

Schürmann

et al. 2014

Journal of Cell Science

112

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“…Because SCUBE2 can regulate VEGF responses both in vitro and in vivo (Figures 1 and 3) and SCUBE proteins can function as coreceptors for signaling receptor serine/threonine kinases or receptor tyrosine kinases, [13][14][15][16] we examined whether SCUBE2 colocalizes and interacts with VEGFR2 in HUVECs. Confocal microscopy and coimmunoprecipitation experiments indeed revealed that VEGF promotes their colocalization at the plasma membrane and enhances the association of SCUBE2 with VEGFR2, peaking at 10 minutes after VEGF stimulation in HUVECs ( Figure 4A To evaluate whether SCUBE2 could indeed increase VEGF binding to VEGFR2, we first produced a functional AP-VEGF Figure 4C).…”

Section: Scube2 Colocalizes and Interacts With Vegfr2 And Potentiatesmentioning

confidence: 99%

Endothelial SCUBE2 Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis

Lin

Chao

Yeh

et al. 2017

ATVB

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Objective— Vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, exerts its proangiogenic action by binding to VEGFR2 (VEGF receptor 2), the activity of which is further modulated by VEGFR2 coreceptors such as neuropilins. However, whether VEGFR2 is regulated by additional coreceptors is not clear. To investigate whether SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2), a peripheral membrane protein expressed in vascular endothelial cells (ECs) known to bind other signaling receptors, functions as a VEGFR2 coreceptor and to verify the role of SCUBE2 in the VEGF-induced angiogenesis. Approach and Results— SCUBE2 lentiviral overexpression in human ECs increased and short hairpin RNA knockdown inhibited VEGF-induced EC growth and capillary-like network formation on Matrigel. Like VEGF, endothelial SCUBE2 was upregulated by hypoxia-inducible factor-1α at both mRNA and protein levels. EC-specific Scube2 knockout mice were not defective in vascular development but showed impaired VEGF-induced neovascularization in implanted Matrigel plugs and recovery of blood flow after hind-limb ischemia. Coimmunoprecipitation and ligand-binding assays showed that SCUBE2 forms a complex with VEGF and VEGFR2, thus acting as a coreceptor to facilitate VEGF binding and augment VEGFR2 signal activity. SCUBE2 knockdown or genetic knockout suppressed and its overexpression promoted the VEGF-induced activation of downstream proangiogenic and proliferating signals, including VEGFR2 phosphorylation and mitogen-activated protein kinase or AKT activation. Conclusions— Endothelial SCUBE2 may be a novel coreceptor for VEGFR2 and potentiate VEGF-induced signaling in adult angiogenesis.

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“…SCUBE3 consists of five motifs: an N-terminal signal peptide, followed by nine copies of EGF (epidermal growth factor)-like repeats, a spacer region, three cysteine-rich domains and a complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain at the C-terminus. SCUBE3 can be cleaved to release the N-terminal EGF-like repeats and the C-terminal CUB domain, which are implicated in protein-protein interactions (Bork and Beckmann, 1993;Rao et al, 1995;Yang et al, 2007). SCUBE3 has recently been discovered to be involved in murine cardiac hypertrophy, through TGF-b1-mediated transcriptional activation (Yang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…SCUBE3 can be cleaved to release the N-terminal EGF-like repeats and the C-terminal CUB domain, which are implicated in protein-protein interactions (Bork and Beckmann, 1993;Rao et al, 1995;Yang et al, 2007). SCUBE3 has recently been discovered to be involved in murine cardiac hypertrophy, through TGF-b1-mediated transcriptional activation (Yang et al, 2007). SCUBE3 has also been implicated in murine embryogenesis and development, as scube3 transcripts are expressed prominently in developing tissues (Haworth et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer

Peck

Chang

et al. 2011

Oncogene

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Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is overexpressed in lung cancer tumor tissues and is correlated with the invasive ability in a lung cancer cell line model. These observations suggest that SCUBE3 may have a role in lung cancer progression. By exogenous SCUBE3 treatment or knockdown of SCUBE3 expression, we found that SCUBE3 could promote lung cancer cell mobility and invasiveness. Knockdown of SCUBE3 expression also suppressed tumorigenesis and cancer metastasis in vivo. The secreted SCUBE3 proteins were cleaved by gelatinases (matrix metalloprotease-2 (MMP-2) and MMP-9) in media to release two major fragments: the N-terminal epidermal growth factor-like repeats and the C-terminal complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain. Both the purified SCUBE3 protein and the C-terminal CUB domain fragment, bound to transforming growth factor-b (TGF-b) type II receptor through the C-terminal CUB domain, activated TGF-b signaling and triggered the epithelial-mesenchymal transition (EMT). This process includes the induction of Smad2/3 phosphorylation, the increase of Smad2/3 transcriptional activity and the upregulation of the expression of target genes involved in EMT and cancer progression (such as TGF-b1, MMP-2, MMP-9, plasminogen activator inhibitor type-1, vascular endothelial growth factor, Snail and Slug), thus promoting cancer cell mobility and invasion. In conclusion, in lung cancer cells, SCUBE3 could serve as an endogenous autocrine and paracrine ligand of TGF-b type II receptor, which could regulate TGF-b receptor signaling and modulate EMT and cancer progression.

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Transgenic overexpression of the secreted, extracellular EGF-CUB domain-containing protein SCUBE3 induces cardiac hypertrophy in mice

Cited by 27 publications

References 34 publications

Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells

Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells

Endothelial SCUBE2 Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis

SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer

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