A mouse knockout library for secreted and transmembrane proteins

Tang, T.F.; Li, Li; Tang, Jerry; Li, Yun; Lin, Wei Yu; Martin, Flavius; Grant, Deanna; Solloway, Mark J.; Parker, Lily; Ye, Weilan; Forrest, William F.; Ghilardi, Nico; Oravecz, Tamás; Platt, Kenneth A.; Rice, Dennis S.; Hansen, Gwenn M.; Abuin, Alejandro; Eberhart, Derek E.; Godowski, Paul J.; Holt, Kathleen H.; Peterson, Andrew; Zambrowicz, Brian; Sauvage, Frédéric J. de

doi:10.1038/nbt.1644

Cited by 308 publications

(295 citation statements)

References 36 publications

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“…These data provide direct support for the conclusion that ANGPTL8 normally acts to increase plasma TAG levels and that it requires ANGPTL3 to do so. Consistent with this notion, Angptl8 −/− mice generated as part of a library of mice with mutations in membrane and secreted proteins had markedly decreased serum TAG levels compared with their sex-matched wild-type littermates (32).…”

Section: Discussionmentioning

confidence: 58%

“…Mutations in DOCK6 cause Adams-Oliver syndrome, a rare disorder affecting skin and limb development, without noted changes in plasma lipid levels (34). Mice lacking Angptl8 were hypotriglyceridemic but no other notable phenotype was observed in a broad phenotypic screen (32). Thus, ANGPTL3 and ANGPTL8 appear to function independently of DOCK7 and DOCK6.…”

Section: Discussionmentioning

confidence: 99%

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Atypical angiopoietin-like protein that regulates ANGPTL3

Quagliarini

Wang

Kozlitina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

403

666

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Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Inactivation of ANGPTL3, a gene located in an intron of DOCK7, results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified another ANGPTL family member, ANGPTL8, which is located in the corresponding intron of DOCK6. A variant in this family member (rs2278426, R59W) was associated with lower plasma LDL-C and HDL-C levels in three populations. ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans. Expression of ANGPTL8 was reduced by fasting and increased by refeeding in both mice and humans. To examine the functional relationship between the two ANGPTL family members, we expressed ANGPTL3 at physiological levels alone or together with ANGPTL8 in livers of mice. Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 coimmunoprecipitated with the N-terminal domain of ANGPTL3 in plasma of these mice. In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3. Consistent with this scenario, expression of ANGPTL8 in Angptl3 −/− mice failed to promote hypertriglyceridemia. Thus, ANGPTL8, a paralog of ANGPTL3 that arose through duplication of an ancestral DOCK gene, regulates postprandial TAG and fatty acid metabolism by controlling activation of its progenitor, and perhaps other ANGPTLs. Inhibition of ANGPTL8 provides a new therapeutic strategy for reducing plasma lipoprotein levels.T he angiopoietin-like (ANGPTL) genes encode a family of secreted proteins with pleiotropic effects on vascular cells (1), lipid metabolism (2), and stem cell biology (3). The family members share a common architecture, comprising an extended N-terminal domain and a C-terminal fibrinogen-like domain. Genetic studies have revealed that two closely related family members, ANGPTL3 and ANGPTL4, play pivotal roles in the trafficking and metabolism of lipids and lipoproteins (4-7). Mutations that disrupt ANGPTL3 are associated with greatly reduced plasma levels of triacylglycerol (TAG) and cholesterol in mice (5) and in humans (4). Mice lacking ANGPTL4 also have markedly reduced levels of plasma TAG and cholesterol (8, 9), and sequence variations in ANGPTL4 are associated with lower plasma TAG levels in humans (7).TAG synthesized in the gut and liver are incorporated into chylomicrons and very low density lipoproteins (VLDL), respectively, and delivered to peripheral tissues where they interact with lipoprotein lipase (LPL). LPL hydrolyzes the TAGs, releasing fatty acids to the adjacent tissues. Other intravascular lipases, including hepatic lipase and endothelial lipase, further remodel lipoprotein particles. Several lines of evidence suggest that ANGPTL3 and ANGPTL4 contribute to the partitioning of TAGs among tissues (2). During fasting, ANGPTL4 levels increase in ad...

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Atypical angiopoietin-like protein that regulates ANGPTL3

Quagliarini

Wang

Kozlitina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

403

666

View full text Add to dashboard Cite

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“…2 CUB (complement factor C1r/C1s, embryonic sea urchin protein uEGF, and bone morphogenetic protein-1)-domain-containing protein 1 (CDCP1) is a transmembrane glycoprotein that is widely expressed in epithelial cells as both full-length 135 kDa and proteolytically processed 70 kDa forms. 9 Although its physiological function is unknown, CDCP1 knockout mice have no obvious reproductive, developmental or survival abnormalities, 10,11 suggesting that targeting this protein in disease settings, including cancer, may be well tolerated. In several tumor types that commonly metastasize via vascular routes, including lung, kidney, pancreas and colon cancer, elevated or cell-surface expression of CDCP1 is associated with poor patient outcome.…”

Section: Introductionmentioning

confidence: 99%

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Harrington

et al. 2015

Oncogene

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Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

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“…Podoplanin is a cell surface protein highly expressed by lymphatic endothelium [22], lymph node stroma [23], spleen stroma [24] and some cancer cells [22]. The interaction of CLEC-2 with podoplanin is important for the separation of blood and lymphatic vessels during development, as both podoplanin and CLEC-2-deficient mice display a bleeding phenotype and atypical vascular connections [25][26][27][28].Besides platelets, CLEC-2 is found on neutrophils, monocytes and liver Kupffer cells [28,29]. The role of CLEC-2 in myeloid cells has not been studied extensively.…”

mentioning

confidence: 99%

“…Besides platelets, CLEC-2 is found on neutrophils, monocytes and liver Kupffer cells [28,29]. The role of CLEC-2 in myeloid cells has not been studied extensively.…”

mentioning

confidence: 99%

CLEC‐2 signaling via Syk in myeloid cells can regulate inflammatory responses

et al. 2011

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Myeloid cells express a plethora of C-type lectin receptors (CLRs) that can regulate immune responses. CLEC-2 belongs to the Dectin-1 sub-family of CLRs that possess an extracellular C-type lectin-like domain and a single intracellular hemITAM motif. CLEC-2 is highly expressed on mouse and human platelets where it signals via Syk to promote aggregation. We generated a monoclonal antibody (mAb) against mouse CLEC-2 and found that CLEC-2 is additionally widely expressed on leukocytes and that its expression is upregulated during inflammation. MAb-mediated crosslinking of CLEC-2 leads to hemI-TAM-dependent signaling via Syk, Ca 21 and NFAT and, in myeloid cells, modulates the effect of toll-like receptor (TLR) agonists to selectively potentiate production of IL-10. A macrophage/dendritic cell-dependent increase in IL-10 is also observed in mice given anti-CLEC-2 mAb together with LPS. Collectively, these data indicate that CLEC-2 is expressed in myeloid cells and acts as a Syk-coupled CLR able to modulate TLR signaling and inflammatory responses.Key words: CLEC-2 . C-type lectin . HemITAM . IL-10 . Syk Supporting Information available online IntroductionSignaling by some members of the C-type lectin receptor (CLR) superfamily plays a key role in innate immunity and in regulation of myeloid cell function [1,2]. A classical example is Dectin-1, which is expressed by macrophages (MØs), neutrophils and dendritic cells (DCs) and acts as a pattern recognition receptor for b-glucans present on fungal and some bacterial cell walls. Dectin-1 signals via a phospho-tyrosine-based hemITAM motif in its intracellular domain that recruits spleen tyrosine kinase (Syk) [3,4]. Dectin-1 signaling through Syk in myeloid cells can variably lead to phagocytosis, production of reactive oxygen species (ROS) and/or induction of innate response genes, including those encoding pro-inflammatory cytokines [5,6]. 3040Pro-inflammatory Dectin-1 signaling requires CARD9-dependent activation of NF-kB [7] although Dectin-1 can also signal to NF-kB via a Syk-independent pathway [8]. Although many DC types are potently activated by Dectin-1 agonists, in other myeloid cells Dectin-1 signaling only weakly activates the proinflammatory gene program [9]. In those cells, Dectin-1 acts primarily in synergy with other innate immune receptors such as toll-like receptors (TLRs) [10,11]. Notably, both Dectin-1 and CARD9 are important for resistance to fungal infection in both mice [7,12,13] and humans [14,15], indicating the importance of the CLR/Syk signaling pathway in immunity.The features of Dectin-1, including type II membrane topology, single Dectin-1-like C-type lectin-like domain and intracellular hemITAM are shared by two other CLRs, DNGR-1 (CLEC9A) and CLEC-2 (CLEC1B). DNGR-1 is selectively expressed by DCs and acts as a receptor for dead cells, facilitating cross-priming to cell-associated antigens [16]. CLEC-2 was first identified in a screen for natural killer (NK) cell receptors and its mRNA was found in myeloid cells and in some NK-cell clones [...

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A mouse knockout library for secreted and transmembrane proteins

Cited by 308 publications

References 36 publications

Atypical angiopoietin-like protein that regulates ANGPTL3

Atypical angiopoietin-like protein that regulates ANGPTL3

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

CLEC‐2 signaling via Syk in myeloid cells can regulate inflammatory responses

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