Introduction to ISM1 (Isthmin-1) in Humans OpenAI o3-deep-research-2025-06-26 93 citations 2025-11-04T02:43:27.967220

Introduction to ISM1 (Isthmin-1) in Humans

Isthmin-1 (ISM1) is a secreted protein encoded by the human ISM1 gene (also known as C20orf82) (www.msesupplies.com). It was originally discovered in Xenopus (frog) embryos at the midbrain–hindbrain organizer (“isthmus”), hence its name (pmc.ncbi.nlm.nih.gov). The ISM1 protein is ~50 kDa in size and is characterized by a signal peptide (for secretion) followed by two conserved domains: a thrombospondin type-1 repeat (TSR1) and an adhesion-associated domain in MUC4 and Other Proteins (AMOP) (pmc.ncbi.nlm.nih.gov) (link.springer.com). The TSR1 (~60 amino acids) is a motif often involved in cell–matrix interactions and TGF-β signaling modulation (link.springer.com). The C-terminal AMOP domain (~160 amino acids) is found only in extracellular proteins (including certain cell-adhesion molecules) and is implicated in cell adhesion and signaling (link.springer.com). These structural features immediately suggested ISM1 might function as an extracellular regulatory factor. Indeed, ISM1 is highly conserved across species – for example, the human and mouse ISM1 proteins share ~98–99% identity in the TSR1 and AMOP domains (link.springer.com) – underscoring its fundamental biological importance.

Expression and Localization: ISM1 is a secreted protein, carrying out its functions in the extracellular space. After being synthesized in the endoplasmic reticulum and Golgi, it is exported outside the cell, where it can diffuse or bind to cell surfaces and the extracellular matrix. In adult humans, ISM1 is expressed in a range of tissues, especially at barrier sites and by certain immune and metabolic cells. Profiling studies have shown high expression in skin and mucosal tissues (e.g. lung) and in subsets of immune cells (pmc.ncbi.nlm.nih.gov). Notably, natural killer (NK) cells, NKT cells, and inflammatory T-cells (Th17 lineage) produce ISM1 (pmc.ncbi.nlm.nih.gov). Its expression in CD4 T-cells is enhanced under Th17-polarizing conditions and suppressed by interferon-γ, suggesting cytokine-regulated expression in immune responses (pmc.ncbi.nlm.nih.gov). ISM1 is also produced by adipose tissue; in fact, it has been identified as an adipokine, a hormone secreted by fat cells (pmc.ncbi.nlm.nih.gov). Circulating ISM1 has been detected in human serum, and recent clinical studies have begun to correlate ISM1 levels with metabolic conditions (for example, higher ISM1 in gestational diabetes and in diabetic albuminuria) (www.ncbi.nlm.nih.gov). Within the body, ISM1 predominantly operates outside cells, binding to specific cell-surface targets (receptors or matrix components) to influence cell behavior. This extracellular mode of action distinguishes ISM1 from intracellular enzymes or structural proteins – it functions as a secreted signaling/regulatory factor. Below, we discuss the known functions of ISM1 in key biological processes, the pathways it influences, and where it carries out these roles, based on current research.

Developmental Functions of ISM1

Role in Embryogenesis: ISM1 has critical functions during early development. It is dynamically expressed in embryos with distinct spatial patterns, hinting at regulatory roles in tissue morphogenesis (pubmed.ncbi.nlm.nih.gov). In Xenopus and chick embryos, ISM1 is highly expressed in organizer regions such as the anterior primitive streak and midbrain-hindbrain boundary during gastrulation (pubmed.ncbi.nlm.nih.gov). One major role of ISM1 in development is the modulation of TGF-β family signaling, specifically the Nodal pathway that controls left-right (L–R) body asymmetry. Experiments have shown that ISM1 acts as an inhibitor of Nodal signaling: it binds directly to Nodal (a TGF-β ligand) and to the Activin receptor ACVR1B (ALK4) via its AMOP domain, preventing Nodal from activating its receptors (pubmed.ncbi.nlm.nih.gov). ISM1 does not broadly block TGF-β/Activin signals – notably it had little effect on TGF-β1, Activin-A, or BMP4 pathways – but it specifically suppresses Nodal-induced SMAD2 phosphorylation (pubmed.ncbi.nlm.nih.gov). Consistent with this, experimental over-expression of ISM1 in chick embryos caused disruptive L–R patterning: treated embryos developed abnormal left-right asymmetry and mis-positioned hearts (pubmed.ncbi.nlm.nih.gov). These findings demonstrate that ISM1’s primary developmental function is as a Nodal antagonist that helps refine embryonic patterning signals. By binding Nodal and its receptor, ISM1 can locally dampen Nodal activity, which is essential for correct asymmetric organ development (pubmed.ncbi.nlm.nih.gov). This mechanism has been proposed to ensure proper heart looping and organ positioning during embryogenesis.

Beyond left-right axis formation, ISM1 may influence other developmental processes. It is co-expressed with key morphogens (for instance, fibroblast growth factor 8) in organizer regions (link.springer.com), suggesting it might interact with or modulate additional signaling centers in the embryo. In zebrafish, ISM1 is essential for normal blood development: knockdown of ism1 impairs the formation of hematopoietic stem and progenitor cells, leading to reduced production of blood lineages (fewer neutrophils, macrophages, and erythrocytes) (pubmed.ncbi.nlm.nih.gov). Morpholino experiments in zebrafish showed that loss of ISM1 disrupts the generation of these stem cells in the embryonic aorta, indicating ISM1 normally supports hematopoietic niche or signaling factors necessary for blood stem cell emergence (pubmed.ncbi.nlm.nih.gov). Although the precise downstream pathway is not fully defined, this conserved requirement points to ISM1 as a growth factor in developmental contexts like hematopoiesis. Taken together, evidence from multiple model organisms highlights ISM1 as a multifunctional embryonic factor. It helps orchestrate developmental signaling pathways – particularly the Nodal/TGF-β pathway – that pattern the early embryo, and it supports the proper formation of organs and cell lineages. These developmental roles are executed extracellularly: ISM1 is secreted by embryonic organizer tissues and acts in the extracellular milieu by binding to growth factor ligands or receptors on cell surfaces (e.g. Nodal and ACVR1B) to modulate signaling (pubmed.ncbi.nlm.nih.gov).

ISM1 in Angiogenesis and Cell Survival

One of the most well-characterized functions of ISM1 is its role as an angiogenesis inhibitor and pro-apoptotic factor in the extracellular environment. ISM1 has potent effects on blood vessel growth: it was identified as a novel secreted anti-angiogenic protein that can block new capillary formation and induce endothelial cell death (link.springer.com) (pubmed.ncbi.nlm.nih.gov). In a landmark study, Xiang et al. (2011) showed that recombinant ISM1 or its isolated C-terminal domain could inhibit endothelial tube formation in vitro and suppress angiogenesis in vivo. When added to cultured endothelial cells, ISM1 (especially the C-terminal AMOP segment) bound to cell surfaces and blocked capillary network formation in a dose- and time-dependent manner, impairing the cells’ migration, adhesion, and survival (link.springer.com). In a mouse model, ISM1 administration dose-dependently inhibited growth-factor–induced neovascularization, demonstrating its anti-angiogenic efficacy in vivo (link.springer.com). Complementing these findings, overexpression of ISM1 in tumor cells strongly suppressed tumor vascularization and growth in mouse xenograft models (pubmed.ncbi.nlm.nih.gov). These experiments establish ISM1 as an endogenous inhibitor of angiogenesis with natural anti-tumor properties.

Mechanisms – Integrin and GRP78 Binding: Molecular studies have elucidated how ISM1, acting outside the cell, triggers apoptosis in endothelial and other cells. ISM1 engages at least two classes of cell-surface molecules: integrins and the receptor/chaperone GRP78 (78 kDa glucose-regulated protein). Integrin αvβ5 on endothelial cells was identified as a low-affinity receptor for ISM1 (pubmed.ncbi.nlm.nih.gov). The ISM1 protein contains an RGD/RKD sequence within its AMOP domain that is predicted to bind integrins (link.springer.com), and indeed ISM1–integrin binding can initiate intracellular signals. For example, ISM1 ligation of αvβ5 integrin on endothelial cells was reported to activate caspase-3 and induce apoptosis (link.springer.com). However, integrin binding alone did not fully explain ISM1’s potent effects. Researchers discovered that ISM1 also targets cell-surface GRP78 as a high-affinity receptor (binding Kd ≈ 8.6 nM) (pubmed.ncbi.nlm.nih.gov). GRP78 (also called BiP) is normally an ER chaperone, but under stress conditions it is often displayed on the plasma membrane of endothelial cells, cancer cells, and some lymphocytes (link.springer.com). Chen et al. (2014) showed that ISM1 binds to exposed GRP78 on target cells, which triggers ISM1 internalization via clathrin-mediated endocytosis and leads to apoptosis (pubmed.ncbi.nlm.nih.gov) (link.springer.com). Once ISM1 is bound to GRP78, the complex is taken into the cell and co-trafficked to the mitochondria (pubmed.ncbi.nlm.nih.gov). Inside the cell, ISM1 localizes to the mitochondrial inner membrane, where it interacts with the adenine nucleotide transporter (ANT) – a carrier that exchanges ADP/ATP across the mitochondrial membrane (link.springer.com). ISM1 essentially blocks ATP export from mitochondria, causing ATP to accumulate in mitochondria and cytosolic energy levels to plummet (link.springer.com). This energetic shutdown activates the intrinsic apoptotic pathway: loss of ATP and mitochondrial dysfunction lead to caspase activation (including caspase-8 and -3) and cell death (link.springer.com) (link.springer.com). Importantly, ISM1’s targeting of GRP78 provides selectivity for stressed or abnormal cells – normal healthy cells express little surface GRP78 and are relatively resistant to ISM1-induced apoptosis (pubmed.ncbi.nlm.nih.gov). In contrast, activated endothelial cells or cancer cells (which upregulate surface GRP78 under tumor and hypoxic stress) are highly susceptible to ISM1’s pro-apoptotic effect (pubmed.ncbi.nlm.nih.gov). Thus, ISM1 acts as a context-dependent “cell death ligand” in the extracellular space, honing in on pathological cells and inducing apoptosis via a unique internalization-to-mitochondria mechanism. This mechanism underlies ISM1’s angiogenesis inhibition (it prunes proliferating blood vessel cells by apoptosis) and its anti-cancer activity by cutting off tumor blood supply and even directly killing tumor cells that express surface GRP78 (pubmed.ncbi.nlm.nih.gov) (link.springer.com).

Beyond endothelial cells, ISM1’s ability to trigger cell death may extend to other contexts. For instance, recent work implicates ISM1 in kidney disease: ISM1 was found to be upregulated in models of glomerulosclerosis, and exposure of kidney podocyte cells to ISM1 reduced their viability and induced apoptosis in vitro (pmc.ncbi.nlm.nih.gov). Low doses of ISM1 activated caspases in cultured podocytes, while higher doses caused mitochondrial membrane depolarization and nuclear translocation of apoptosis-inducing factor (AIF), indicative of severe mitochondrial injury (pmc.ncbi.nlm.nih.gov). These observations suggest that aberrant ISM1 expression can contribute to tissue injury (in this case, podocyte loss and proteinuric kidney disease) through the same apoptosis pathway identified in endothelial cells. In cancer biology, there are also indications that ISM1 might influence the immune microenvironment of tumors. A 2021 study found that ISM1 expression correlates with upregulation of immunosuppressive molecules (like the checkpoint receptors TIM-3 and CTLA-4) in certain cancers (link.springer.com). This raises the possibility that ISM1 could dampen anti-tumor immune responses, although more research is needed to clarify this role. In summary, ISM1 functions extracellularly as a multifaceted regulator of cell survival: it can limit pathological angiogenesis and tumor growth by directly inducing apoptosis of endothelial or tumor cells, and it might indirectly shape immune or inflammatory environments in disease. The key molecular players in these processes are cell-surface integrins and GRP78, which serve as ISM1’s entry points to execute its pro-apoptotic program outside-in.

Metabolic Role of ISM1 as an Adipokine

In addition to developmental and anti-angiogenic functions, ISM1 has emerged as a hormone-like factor in metabolism. In 2021, Jiang et al. reported ISM1 as a novel adipokine involved in glucose and lipid homeostasis (pmc.ncbi.nlm.nih.gov). Adipose (fat) tissue was found to secrete ISM1, and this secreted ISM1 acts on other tissues to regulate metabolic processes. Notably, ISM1 can enhance glucose uptake into adipocytes and improve systemic glucose tolerance (pmc.ncbi.nlm.nih.gov). Mice lacking ISM1 (germline knockout models) showed impaired glucose handling – they had reduced basal and insulin-stimulated glucose uptake in adipose tissue, developed worse glucose intolerance, and exhibited decreased insulin sensitivity (pmc.ncbi.nlm.nih.gov). These phenotypes indicate that endogenous ISM1 normally promotes insulin-responsive glucose disposal. Strikingly, ISM1 was shown to trigger the PI3K–Akt signaling pathway in adipose tissue independently of the insulin receptor (pmc.ncbi.nlm.nih.gov). In other words, ISM1 can activate the same key downstream pathway as insulin (PI3K/Akt, which drives glucose uptake) but does so via a distinct receptor mechanism that does not involve the insulin or IGF-1 receptors (pmc.ncbi.nlm.nih.gov). This insulin-independent route is significant because it means ISM1 can stimulate glucose uptake even when insulin signaling is impaired. Mechanistically, although the exact receptor for ISM1 in metabolic tissues remains to be identified, the outcome is clear: ISM1 binding on adipocytes triggers PI3K and Akt phosphorylation, leading to increased glucose transporter activity and glucose uptake into the cells (pmc.ncbi.nlm.nih.gov). In this way, ISM1 acts as an “insulin-like” hormone in adipose tissue, augmenting glucose clearance from the blood (pubmed.ncbi.nlm.nih.gov).

Importantly, ISM1’s metabolic effects are not a mere duplicate of insulin – ISM1 has distinct actions on lipid metabolism that complement its glucose-lowering function. While insulin tends to promote lipogenesis (fat storage) in the liver, ISM1 does the opposite. The presence of ISM1 shifts hepatocytes from a lipid-storage program to a protein-synthesis program, thereby inhibiting hepatic lipid synthesis and accumulation (pmc.ncbi.nlm.nih.gov). In experimental models, ISM1 treatment reduced triglyceride accumulation in liver cells, alleviating fatty liver changes. This dual action – increasing peripheral glucose uptake and reducing liver fat – positions ISM1 as a beneficial metabolic regulator. Indeed, in obese diabetic mice, therapeutic administration of recombinant ISM1 significantly improved hyperglycemia and enhanced insulin sensitivity, while also ameliorating hepatic steatosis (fatty liver) (pmc.ncbi.nlm.nih.gov). For example, mice on a high-fat diet treated with ISM1 had lower blood glucose levels and less fat buildup in the liver compared to controls (pmc.ncbi.nlm.nih.gov). These findings were described as revealing “an unexpected, bioactive protein hormone” with potential to tackle both diabetes and fatty liver disease simultaneously (pmc.ncbi.nlm.nih.gov). In essence, ISM1 functions as a metabolic hormone that links adipose tissue to systemic energy regulation. It carries out this role in the extracellular space by circulating from fat to target organs: in adipose tissue it acts in an autocrine/paracrine fashion to enhance glucose uptake, and in the liver it likely binds to cell-surface receptors that alter metabolic signaling, tilting the balance away from fat storage (pmc.ncbi.nlm.nih.gov). The discovery of ISM1’s metabolic role is quite recent, and ongoing research is focused on identifying its receptor and understanding how it integrates into known metabolic pathways. Nevertheless, its ability to activate PI3K–Akt without engaging the insulin receptor marks it as a unique lever in glucose metabolism. Additionally, its insulin-sensitizing and lipid-lowering effects have attracted interest in ISM1 as a therapeutic target for metabolic disorders. Experts note that harnessing ISM1 or its pathway could lead to treatments that improve glycemic control without the side effect of promoting fat storage (pmc.ncbi.nlm.nih.gov) (www.frontiersin.org).

Other Biological Roles and Emerging Insights

Beyond the major roles described above, ISM1 appears to have ancillary functions in immune regulation and tissue homeostasis, though these are still being elucidated. The presence of ISM1 in skin and mucosal sites, and its induction in Th17 cells, suggests it may contribute to barrier immunity or inflammation (pmc.ncbi.nlm.nih.gov). A recent study in fish provides evidence that ISM1 can act as an innate immune modulator: in zebrafish, ISM1 expression was shown to limit viral replication and promote antiviral responses by enhancing the production of interferons and antiviral genes via the TBK1–IRF3 signaling pathway (www.frontiersin.org). In that model, increasing ISM1 led to higher interferon (IFN) levels and up-regulation of antiviral effectors like Mx, thereby helping the host control infection (www.frontiersin.org). This finding hints that ISM1 might function as a conserved antiviral factor, perhaps by serving as a danger signal or by influencing cytokine signaling in infected tissues. Whether human ISM1 plays a similar role in antiviral defense or inflammation is an area of active inquiry. Its expression by NK cells and certain T-cells could mean ISM1 participates in the crosstalk between immune cells and the vasculature or epithelium during inflammation. Interestingly, because ISM1 can induce apoptosis via GRP78, there is speculation that immune cells secreting ISM1 might use it to eliminate nearby cells (for instance, NK cells might secrete ISM1 to help kill tumor endothelial cells or infected cells expressing surface GRP78). Some researchers have also noted that ISM1 can influence inflammatory signaling pathways. For example, ISM1 has been linked to changes in the expression of inflammatory cytokines and checkpoint molecules in cancer models (link.springer.com) (link.springer.com). Although details remain to be worked out, ISM1 could thus be involved in immune suppression or activation depending on context, making it a potentially important mediator in the tumor microenvironment or autoimmune settings.

From a clinical standpoint, these diverse activities make ISM1 relevant to multiple diseases. Its role in cancer is double-edged: on one hand ISM1 is anti-angiogenic and pro-apoptotic to tumors (a desirable therapeutic trait), but tumors might also exploit ISM1’s apoptosis pathway to evade immune attack (if, for example, tumor-derived ISM1 suppressed immune cell function) (link.springer.com) (www.frontiersin.org). Nonetheless, the prevailing view is that ISM1 or its functional peptides could be harnessed as anti-cancer agents. A cyclic peptide derived from the ISM1 AMOP domain (termed “BC71”) has already been tested: it binds cell-surface GRP78 and mimics ISM1’s apoptotic effect, activating p53 and caspase-8 to kill endothelial and cancer cells (link.springer.com) (link.springer.com). In mice, this peptide inhibited angiogenesis and tumor growth without systemic toxicity in early studies (link.springer.com) (link.springer.com). Such approaches underscore ISM1’s therapeutic potential. Likewise in metabolic disease, ISM1 is being explored as a therapeutic target or biomarker. As noted, raising ISM1 levels in mice improved diabetes and fatty liver outcomes (pmc.ncbi.nlm.nih.gov). However, human data are still preliminary. A 2022 review highlighted that no clinical trials have yet evaluated ISM1 therapy in humans and suggested this as a promising research direction (www.frontiersin.org). Observational studies have measured ISM1 in patient sera: one report found elevated ISM1 in people with obesity and a correlation with visceral fat distribution, hinting that ISM1 might reflect or influence adipose tissue function . Another study noted higher ISM1 levels in gestational diabetes, proposing ISM1 as a potential biomarker for metabolic stress in pregnancy (www.ncbi.nlm.nih.gov). These clinical correlations need further validation, but they align with ISM1’s identified role in metabolism.

Conclusion and Outlook

In summary, ISM1 (Isthmin-1) is a multifunctional secreted protein that plays diverse roles in human biology, from guiding embryonic development to regulating blood vessel growth, immune responses, and metabolism. At its core, ISM1’s primary function is to act as an extracellular mediator that binds specific targets (growth factors, receptors, or integrins) and thereby modulates key signaling pathways. In embryos, ISM1 is a precise inhibitor of Nodal/TGF-β signals, ensuring proper left-right patterning and contributing to organogenesis (pubmed.ncbi.nlm.nih.gov). In the vascular system, ISM1 serves as a context-dependent pro-apoptotic factor, targeting surface GRP78 to trigger endothelial and tumor cell apoptosis, which in turn inhibits pathological angiogenesis (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). As a hormone, ISM1 functions as an insulin-independent metabolic regulator, activating PI3K–Akt signaling in adipose tissue to promote glucose uptake and concurrently protecting against fatty liver by restraining lipogenesis (pmc.ncbi.nlm.nih.gov). These roles are carried out in the extracellular space – whether in the interstitial matrix of developing tissues, the bloodstream near insulin-sensitive organs, or the tumor microenvironment, ISM1 exerts its effects by binding outside of cells and transducing signals inward. This extrinsic mode of action is a unifying theme, even though the outcomes differ by context (developmental patterning vs. apoptosis vs. metabolism).

Crucially, experimental evidence underpins each of these functions: loss-of-function and gain-of-function studies in animals have demonstrated ISM1’s importance (e.g. chick embryo experiments for L-R asymmetry (pubmed.ncbi.nlm.nih.gov), zebrafish morphants for hematopoiesis (pubmed.ncbi.nlm.nih.gov), mouse knockouts for glucose homeostasis (pmc.ncbi.nlm.nih.gov), and xenograft models for angiogenesis (pubmed.ncbi.nlm.nih.gov)). Biochemical assays and structural inferences have identified how ISM1 engages with its partners – for example, the presence of a TSR1 domain foreshadowed TGF-β pathway involvement (link.springer.com), and indeed ISM1 specifically binds the Nodal ligand to modulate that pathway (pubmed.ncbi.nlm.nih.gov). Similarly, the AMOP domain contains an RGD-like motif, and ISM1 was found to bind an RGD-binding integrin (αvβ5) on endothelial cells (link.springer.com). The discovery of surface GRP78 as an ISM1 receptor was informed by the notion that ISM1 induces apoptosis selectively in stressed cells; this led researchers to identify GRP78 – a stress-inducible surface protein – as the high-affinity interaction that explains ISM1’s selective toxicity (pubmed.ncbi.nlm.nih.gov). Such structure-function relationships continue to be an area of interest, as scientists seek to determine if ISM1’s metabolic receptor is another integrin, a signaling co-receptor, or an unknown receptor that connects ISM1 to PI3K activation.

Given ISM1’s involvement in critical pathways, current research is highly active (especially in the past few years). Reviews in 2023–2024 describe ISM1 as a “multifunctional secreted protein” at the intersection of development, angiogenesis, metabolism, and immunity (pubmed.ncbi.nlm.nih.gov). Its ability to regulate cell proliferation, migration, and the immune milieu in cancer has been highlighted, as has its role as a newly identified insulin-like adipokine (pubmed.ncbi.nlm.nih.gov). Experts in the field (Liang et al., 2024) note that while much progress has been made, “the biological function of ISM-1 remains largely unknown” in the sense that new roles may yet be discovered and the full molecular network of ISM1’s action is not fully mapped (pubmed.ncbi.nlm.nih.gov). Moving forward, key questions include identifying the receptors and signaling cascades through which ISM1 operates in metabolic tissues and immune cells, understanding how ISM1 expression is regulated in various physiological and disease states, and exploring therapeutic applications. There is optimism that harnessing ISM1 could lead to novel treatments: for instance, ISM1 or its analogs might be used to starve tumors of blood vessels or to improve metabolic syndrome without the side-effects of excess insulin (pmc.ncbi.nlm.nih.gov) (www.frontiersin.org). In summary, ISM1 is a compelling example of a gene product with pleiotropic yet well-defined functions – a secreted adapter that links developmental cues, vascular homeostasis, and metabolic control. Ongoing research, armed with precise structural and functional studies, is expected to fully elucidate ISM1’s role in human biology and disease, potentially translating this knowledge into clinical interventions in the future (pubmed.ncbi.nlm.nih.gov) (www.frontiersin.org).

References: (Key studies and reviews are cited in text above, with publication year and DOI/PubMed where available.)

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  21. AnnotationURLCitation(end_index=8504, start_index=8321, title='Isthmin 1 (ism1) is required for normal hematopoiesis in developing zebrafish - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/29758043/#:~:text=numbers%20of%20neutrophils%2C%20macrophages%2C%20and,investigated%20for%20potential%20clinical%20utility')
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  24. AnnotationURLCitation(end_index=10089, start_index=9965, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=Isthmin%20,this%20work%2C%20we%20report%20the')
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  27. AnnotationURLCitation(end_index=11327, start_index=11203, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=Isthmin%20,this%20work%2C%20we%20report%20the')
  28. AnnotationURLCitation(end_index=11986, start_index=11842, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=cell%20%28EC%29%20apoptosis,Normal%20cells%20and%20benign%20tumor')
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  31. AnnotationURLCitation(end_index=12950, start_index=12793, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=affinity%20receptor%20for%20ISM%2C%20the,Normal%20cells%20and%20benign%20tumor')
  32. AnnotationURLCitation(end_index=13283, start_index=13135, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=protein%2C%20GRP78%2C%20promotes%20proper%20protein,Chen')
  33. AnnotationURLCitation(end_index=13607, start_index=13460, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=identification%20of%20cell,membrane%20and%20blocks%20ATP%20transport')
  34. AnnotationURLCitation(end_index=13755, start_index=13608, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=2003%20%3B%20Tsai%20et%20al,level%20of%20ATP%20in%20the')
  35. AnnotationURLCitation(end_index=14009, start_index=13859, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=cells%20tend%20to%20express%20low,GRP78%20to%20trigger%20apoptosis%20by')
  36. AnnotationURLCitation(end_index=14350, start_index=14218, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=soluble%20ISM1%20binds%20to%20GRP78%2C,3')
  37. AnnotationURLCitation(end_index=14623, start_index=14491, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=soluble%20ISM1%20binds%20to%20GRP78%2C,3')
  38. AnnotationURLCitation(end_index=14971, start_index=14805, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=ISM1%20binds%20to%20av%CE%B25%20and,8%20signaling%2C%20causing%20apoptosis')
  39. AnnotationURLCitation(end_index=15073, start_index=14972, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=et%20al,3')
  40. AnnotationURLCitation(end_index=15420, start_index=15273, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=identification%20of%20cell,membrane%20and%20blocks%20ATP%20transport')
  41. AnnotationURLCitation(end_index=15748, start_index=15601, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=identification%20of%20cell,membrane%20and%20blocks%20ATP%20transport')
  42. AnnotationURLCitation(end_index=16337, start_index=16198, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=cell%20%28EC%29%20apoptosis,and%20are%20resistant%20to%20ISM')
  43. AnnotationURLCitation(end_index=16485, start_index=16338, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=2003%20%3B%20Tsai%20et%20al,level%20of%20ATP%20in%20the')
  44. AnnotationURLCitation(end_index=16976, start_index=16814, title='The Angiogenesis Inhibitor Isthmin-1 (ISM1) Is Overexpressed in Experimental Models of Glomerulopathy and Impairs the Viability of Podocytes - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9916724/#:~:text=with%20low%20doses%20of%20recombinant,in%20the%20progression%20of%20glomerular')
  45. AnnotationURLCitation(end_index=17368, start_index=17206, title='The Angiogenesis Inhibitor Isthmin-1 (ISM1) Is Overexpressed in Experimental Models of Glomerulopathy and Impairs the Viability of Podocytes - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9916724/#:~:text=with%20low%20doses%20of%20recombinant,in%20the%20progression%20of%20glomerular')
  46. AnnotationURLCitation(end_index=17996, start_index=17871, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=match%20at%20L706%20T,mesenchymal')
  47. AnnotationURLCitation(end_index=19034, start_index=18861, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=Here%2C%20Zewen%20Jiang%20et%20al,therapeutic%20opportunity%20to%20simultaneously%20treat')
  48. AnnotationURLCitation(end_index=19412, start_index=19262, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=we%20identify%20Isthmin,Furthermore%2C%20therapeutic%20dosing%20of')
  49. AnnotationURLCitation(end_index=19805, start_index=19655, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=we%20identify%20Isthmin,Furthermore%2C%20therapeutic%20dosing%20of')
  50. AnnotationURLCitation(end_index=20210, start_index=20042, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=Ism1%20ablation%20results%20in%20impaired,induced%20obese%20mice%20and%20ameliorates')
  51. AnnotationURLCitation(end_index=20561, start_index=20428, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=Ism1%20in%20glucose%20regulation,These%20findings')
  52. AnnotationURLCitation(end_index=21142, start_index=20974, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=Ism1%20ablation%20results%20in%20impaired,induced%20obese%20mice%20and%20ameliorates')
  53. AnnotationURLCitation(end_index=21423, start_index=21263, title='Isthmin: A multifunctional secretion protein - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/37979212/#:~:text=development%20of%20cancer%20by%20regulating,1%20remains%20largely%20unknown.%20In')
  54. AnnotationURLCitation(end_index=22017, start_index=21860, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=Ism1%20in%20glucose%20regulation,diabetes%20and%20fatty%20liver%20disease')
  55. AnnotationURLCitation(end_index=22626, start_index=22488, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=receptors,hormone%20that%20might%20have%20simultaneous')
  56. AnnotationURLCitation(end_index=22907, start_index=22769, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=receptors,hormone%20that%20might%20have%20simultaneous')
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  58. AnnotationURLCitation(end_index=23807, start_index=23665, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=Ism1%20ablation%20results%20in%20impaired,These%20findings')
  59. AnnotationURLCitation(end_index=24591, start_index=24434, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=Ism1%20in%20glucose%20regulation,diabetes%20and%20fatty%20liver%20disease')
  60. AnnotationURLCitation(end_index=24806, start_index=24592, title='Frontiers | A brief overview about the adipokine: Isthmin-1', type='url_citation', url='https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.939757/full#:~:text=have%20evaluated%20the%20therapeutic%20potential,goal%20for%20the%20near%20future')
  61. AnnotationURLCitation(end_index=25329, start_index=25176, title='Isthmin 1 Is a Secreted Protein Expressed in Skin, Mucosal Tissues, and NK, NKT, and Th17 Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4186767/#:~:text=predicted%20%E2%88%BC50,lymphocyte%20effector%20functions%20and%20may')
  62. AnnotationURLCitation(end_index=25827, start_index=25627, title='Frontiers | A brief overview about the adipokine: Isthmin-1', type='url_citation', url='https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.939757/full#:~:text=ISM1%20might%20be%20a%20new,expression%20of%20ISM1%20in%20zebrafish')
  63. AnnotationURLCitation(end_index=26191, start_index=25991, title='Frontiers | A brief overview about the adipokine: Isthmin-1', type='url_citation', url='https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.939757/full#:~:text=ISM1%20might%20be%20a%20new,expression%20of%20ISM1%20in%20zebrafish')
  64. AnnotationURLCitation(end_index=27305, start_index=27145, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=of%20multiple%20organs,relevant%20research%20results%20from%20recent')
  65. AnnotationURLCitation(end_index=27454, start_index=27306, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=protein%2C%20GRP78%2C%20promotes%20proper%20protein,Chen')
  66. AnnotationURLCitation(end_index=28214, start_index=28066, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=protein%2C%20GRP78%2C%20promotes%20proper%20protein,Chen')
  67. AnnotationURLCitation(end_index=28422, start_index=28215, title='Frontiers | A brief overview about the adipokine: Isthmin-1', type='url_citation', url='https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.939757/full#:~:text=that%20ISM1%20may%20be%20a,potential%20therapeutic%20target%20for%20cancer')
  68. AnnotationURLCitation(end_index=28936, start_index=28769, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=addition%2C%20BC71%20in%20the%20AMOP,8%20signaling%2C%20causing%20apoptosis')
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  71. AnnotationURLCitation(end_index=29536, start_index=29389, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=2003%20%3B%20Tsai%20et%20al,level%20of%20ATP%20in%20the')
  72. AnnotationURLCitation(end_index=29906, start_index=29772, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=receptors,diabetes%20and%20fatty%20liver%20disease')
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  74. AnnotationURLCitation(end_index=30817, start_index=30688, title='ISM1 isthmin 1 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/140862#:~:text=1,positively%20and%20independently%20correlated%20with')
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  76. AnnotationURLCitation(end_index=32045, start_index=31878, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=affinity%20receptor%20for%20ISM%2C%20the,essential%20for%20its%20proapoptotic%20activity')
  77. AnnotationURLCitation(end_index=32196, start_index=32046, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=cells%20tend%20to%20express%20low,GRP78%20to%20trigger%20apoptosis%20by')
  78. AnnotationURLCitation(end_index=32569, start_index=32427, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=Ism1%20ablation%20results%20in%20impaired,These%20findings')
  79. AnnotationURLCitation(end_index=33371, start_index=33219, title='ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/31171630/#:~:text=inhibitor%20of%20NODAL%20signaling,ACVR1B%20through%20its%20AMOP%20domain')
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  81. AnnotationURLCitation(end_index=33786, start_index=33636, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=we%20identify%20Isthmin,Furthermore%2C%20therapeutic%20dosing%20of')
  82. AnnotationURLCitation(end_index=33950, start_index=33826, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=Isthmin%20,this%20work%2C%20we%20report%20the')
  83. AnnotationURLCitation(end_index=34290, start_index=34133, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=Stuelten%20and%20Zhang%202021%29,found%20that%20ISM1%20caused%20a')
  84. AnnotationURLCitation(end_index=34528, start_index=34369, title='ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/31171630/#:~:text=embryo%2C%20suggested%20that%20ISM1%20may,ACVR1B%20through%20its%20AMOP%20domain')
  85. AnnotationURLCitation(end_index=34795, start_index=34664, title='Advances in research of biological functions of Isthmin-1 | Journal of Cell Communication and Signaling', type='url_citation', url='https://link.springer.com/article/10.1007/s12079-023-00732-3#:~:text=The%20AMOP%20structural%20domain%20is,C')
  86. AnnotationURLCitation(end_index=35252, start_index=35085, title='Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24464222/#:~:text=affinity%20receptor%20for%20ISM%2C%20the,essential%20for%20its%20proapoptotic%20activity')
  87. AnnotationURLCitation(end_index=35928, start_index=35774, title='Isthmin: A multifunctional secretion protein - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/37979212/#:~:text=Xenopus%20gastrula%20embryos,and%20physiological%20functions%20of%20isthmin')
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  89. AnnotationURLCitation(end_index=36705, start_index=36538, title='Isthmin: A multifunctional secretion protein - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/37979212/#:~:text=development%20of%20cancer%20by%20regulating,and%20treatment%20strategies%20for%20various')
  90. AnnotationURLCitation(end_index=37399, start_index=37234, title='Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8429235/#:~:text=lipogenic%20to%20a%20protein%20synthesis,diabetes%20and%20fatty%20liver%20disease')
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