The Soluble Form of LR11 Protein Is a Regulator of Hypoxia-induced, Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Adhesion of Immature Hematological Cells

Nishii, Keigo; Nakaseko, Chiaki; Jiang, Meizi; Shimizu, Naomi; Takeuchi, Masahiro; Schneider, Wolfgang J.; Bujo, Hideaki

doi:10.1074/jbc.m112.442491

Cited by 28 publications

(21 citation statements)

References 55 publications

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“…Previous studies also suggest that it is the mature form of sorLA that is fully functional, and interestingly, the extracellular shedding of sorLA only occurs when sorLA interacts with TACE (TNFα Converting Enzyme) at the cell surface (16,19). The role of sorLA shedding remains largely elusive, however, the shed ectodomain appears to influence signaling pathways and to regulate cell adhesion (20,21).…”

Section: Introductionmentioning

confidence: 99%

Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer’s-associated protein sorLA

Christensen

Narimatsu

Simoes

et al. 2020

Preprint

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The sorting receptor sorLA encoded by the SORL1 gene is implicated in Alzheimer’s disease (AD) pathogenesis. Genetic studies have identified AD-associated SORL1 mutations and the expression of sorLA in AD brains is reported to be reduced. SorLA is a receptor of the retromer trafficking complex and functions at the endosome, and deficiency in sorLA phenocopies the endosomal pathologies found in AD. SorLA undergoes posttranslational modifications and maturation with ultimate ectodomain shedding, however knowledge of these processes remains limited. Here we demonstrate that sorLA exists at the cell membrane in two forms, an immature and a mature form, characterized by distinct N-glycosylation profiles. The mature sorLA form has acquired complex type N-glycans and is shed from the cell surface by the TACE juxtmembrane cleavage. The immature form of sorLA present at the cell surface is shown to have immature ER-type N-glycans (high-mannose type susceptible to endo H) and does not undergo shedding, however, upon endocytosis and recycling to the cell surface via endosomal trafficking pathways the immature sorLA form acquires complex-type N-glycans. These results suggest an unusual secretion model for sorLA whereby that immature sorLA first traffics to the cell membrane without acquiring Golgi processing of N-glycans, and only upon retrograde trafficking does sorLA acquire normal Golgi maturation of N-glycans and become susceptible to TACE regulated shedding. Supportive evidence for this model include a sorLA mutant with deficient endosomal trafficking and in vivo studies demonstrating requirement of retromer for sorLA trafficking in the brain of retromer VPS26 deficient mice. Collectively, our study establishes the role endosomal trafficking plays in sorLA’s normal maturation, and point to impaired maturation as a signature of AD-associated sorLA dysfunction.

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Section: Introductionmentioning

confidence: 99%

Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer’s-associated protein sorLA

Christensen

Narimatsu

Simoes

et al. 2020

Preprint

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“…18 We previously reported that HIF-1α binds to the proximal 144-bp LR11 promoter in a region where a potential HIF-1-binding site can be induced by hypoxia. 19 The present study found that HIF-1α knockdown decreased LR11 expression under hypoxia, indicating that HIF-1α plays a key role in LR11 expression under such conditions.…”

Section: Lr11 Deletion Prevents Pulmonary Vascular Remodeling Via Hifmentioning

confidence: 68%

“…Although we found that sLR11 alone induced the proliferation of cultured PASMC, endothelial cells and immature cells such as hematopoietic stem and progenitor cells might also regulate serum sLR11 levels in pulmonary hypertension. 19,26 We previously showed that sLR11 could be a useful biomarker of conditions such as atherosclerosis, 17 large B-cell lymphoma, 27 non-Hodgkin lymphoma, 28 follicular lymphoma, 29 diabetic retinopathy, 30 and acute coronary syndrome. 31 Overall, sLR11 might serve as a potentially noninvasive and objective parameter of responses to therapy, although further investigation using other models of PH is essential to define how much circulating sLR11 levels reflect the pathological conditions of PASMC in patients.…”

Section: Cd38mentioning

confidence: 99%

“…17,19,25 Considering the difficulties involved in trying to identify the major source of cells that regulate circulating sLR11 levels, we analyzed LR11 expression in rat monocrotaline and mouse hypoxia models. Levels of LR11 protein increased in both models, indicating that LR11 expression increased in the present models of PAH under hypoxia and under treatment with monocrotaline (data not shown).…”

Section: Cd38mentioning

confidence: 99%

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Deletion of LR11 Attenuates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation With Medial Thickening in Mice

Jiang

Konishi

Nurwidya

et al. 2016

ATVB

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Objective-We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension. Approach and Results-The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1α was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11−/− mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11 −/− mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor-1α was increased in cultured SMC under hypoxic conditions, and hypoxia-inducible factor-1α knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure. Conclusions-LR11 regulated SMC proliferation during the progression of hypoxia-induced medial thickening in mice.The findings obtained from mice, together with those in humans, indicate that sLR11 could serve as a novel biomarker that reflects the pathophysiology of proliferating medial SMC in pulmonary arterial hypertension. (Arterioscler Thromb

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“…Hypoxia could disrupt tissue integrity through repression of E-cadherin expression (Fu et al, 2014). Hypoxia could also promote proteolytic activity at the invasive front and alter the interactions between integrins and components of the extracellular matrix (Nishii et al, 2013). The high HIFPH3 expression in NSCLC could facilitate metastasis by regulating HIF-1α, resulting in hypoxia responses in tumor.…”

Section: Discussionmentioning

confidence: 99%

Expression of Hypoxia-inducible Factor Prolyl Hydroxylase 3 HIFPH3 in Human Non-small Cell Lung Cancer (NSCLC) and Its Correlation with Prognosis

Chu

Zhu²,

Liu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Purpose: To investigate the expression of hypoxia-inducible factor prolyl hydroxylase 3 (HIFPH3) in non-small cell lung cancer (NSCLC) and explore the correlation of HIFPH3 expression with lymph node metastasis and microvessel density (MVD). Materials and Methods: A total of 73 cases of NSCLC specimens, 24 cases of paracancerous tissues, and 20 normal pulmonary tissues were collected for HIFPH3 and CD31 immunohistochmical (IHC) study. Microvessel density (MVD) of the NSCLC tissues was also determined based on the expression of CD31. Results: The expression of HIFPH3 in carcinoma tissue was statistically higher than para-cancerous and normal pulmonary tissues (χ 2 =48.806, p<0.05). Compared withthe negative lymph node metastasis group, the lymph node metastasis group showed significantly higher HIFPH3 expression (χ 2 =6.300, p<0.05). The strong HIFPH3+group displayed a significantly higher MVD than weak HIFPH3+ and HIFPH3-groups (p<0.05). No differences in positive HIFPH3 expression were noted regarding the tumor diameter, age, smoking status, gender of NSCLC patients, tumor size, histopathology, or differentiation. Conclusions: HIFPH3 expression in human NSCLC lesions is significantly higher than that in para-cancerous and normal lung tissues and is positively associated with lymph node metastasis and MVD.

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The Soluble Form of LR11 Protein Is a Regulator of Hypoxia-induced, Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Adhesion of Immature Hematological Cells

Cited by 28 publications

References 55 publications

Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer’s-associated protein sorLA

Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer’s-associated protein sorLA

Deletion of LR11 Attenuates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation With Medial Thickening in Mice

Expression of Hypoxia-inducible Factor Prolyl Hydroxylase 3 HIFPH3 in Human Non-small Cell Lung Cancer (NSCLC) and Its Correlation with Prognosis

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