Isthmin-1 is a secreted glycoprotein (~50-60 kDa) containing a thrombospondin type-1 repeat (TSR1) and a C-terminal AMOP (adhesion-associated domain in MUC4 and other proteins) domain. ISM1 functions as an extracellular signaling factor with multiple biological roles. Its primary established function is as an angiogenesis inhibitor that blocks endothelial cell proliferation, migration, and tube formation. ISM1 binds to cell-surface GRP78 (high affinity, Kd ~8.6 nM) and integrin alphaVbeta5 (low affinity) to trigger apoptosis in activated endothelial cells and tumor cells. The protein is internalized via clathrin-mediated endocytosis and traffics to mitochondria where it blocks ATP transport via the adenine nucleotide transporter. ISM1 also functions as a novel adipokine that promotes glucose uptake in adipocytes and skeletal muscle through PI3K-Akt signaling independent of insulin/IGF receptors. In development, ISM1 acts as a Nodal antagonist that modulates TGF-beta family signaling for proper left-right patterning. Expression is detected in lung, brain, kidney, heart, skeletal muscle, adipose tissue, and immune cells (NK cells, NKT cells, Th17 cells). ISM1 binds integrin alpha8beta1 in kidney mesenchyme to regulate branching morphogenesis during nephrogenesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016525 negative regulation of angiogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: ISM1 is a well-established angiogenesis inhibitor. The protein blocks endothelial cell proliferation, migration, and tube formation through binding to cell-surface receptors (GRP78 and integrin alphaVbeta5), triggering apoptosis. This anti-angiogenic function is supported by extensive experimental evidence from multiple studies. Reason: This is a core function of ISM1. The anti-angiogenic activity has been demonstrated in vitro and in vivo. Recombinant ISM1 or its C-terminal AMOP domain inhibits endothelial tube formation and suppresses angiogenesis in mouse models. Overexpression of ISM1 in tumor cells strongly suppressed tumor vascularization and growth in xenograft models. The IBA annotation based on phylogenetic inference is well-supported by primary literature. Supporting Evidence: PMID:24464222 Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. file:human/ISM1/ISM1-deep-research-falcon.md 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. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: ISM1 is a secreted protein with a signal peptide that is exported to the extracellular space where it functions as a signaling factor. It is detected in circulation (serum) and associates with the extracellular matrix. Reason: The secreted localization is fundamental to ISM1 function. UniProt annotation indicates secreted status, and this is confirmed by detection of circulating ISM1 in human serum in multiple clinical studies. ISM1 carries out its functions extracellularly by binding to cell-surface receptors. Supporting Evidence: file:human/ISM1/ISM1-uniprot.txt SUBCELLULAR LOCATION - Secreted file:human/ISM1/ISM1-deep-research-falcon.md ISM1 is a secreted protein detectable in circulation in several human studies and also binds extracellular matrix |
| GO:0005178 integrin binding | TAS PMID:24464222 Isthmin targets cell-surface GRP78 and triggers apoptosis vi... | NEW | Summary: ISM1 binds to integrins including alphaVbeta5 on endothelial cells and alpha8beta1 on kidney mesenchyme. The AMOP domain contains an RKD/KGD motif that mediates integrin interactions. Reason: Integrin binding is a key molecular function of ISM1 that mediates both its anti-angiogenic effects (via alphaVbeta5) and developmental roles (via alpha8beta1). This annotation should be added based on strong experimental evidence. Supporting Evidence: PMID:24464222 Although alphavbeta5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. file:human/ISM1/ISM1-deep-research-falcon.md integrin alpha8beta1 was identified as an ISM1 receptor in developing kidney mesenchyme, transmitting FAK/Akt/ERK signaling and promoting mesenchymal condensation |
| GO:2000353 positive regulation of endothelial cell apoptotic process | TAS PMID:24464222 Isthmin targets cell-surface GRP78 and triggers apoptosis vi... | NEW | Summary: ISM1 induces apoptosis specifically in activated endothelial cells by binding to cell-surface GRP78, followed by internalization and mitochondrial dysfunction. Reason: This is a key mechanism by which ISM1 inhibits angiogenesis. The protein triggers endothelial cell apoptosis through a specific pathway involving GRP78 binding, clathrin-mediated endocytosis, and mitochondrial ATP transport blockade. Supporting Evidence: PMID:24464222 we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (Kd=8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. PMID:24464222 Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. |
| GO:0005179 hormone activity | TAS PMID:34348115 Isthmin-1 is an adipokine that promotes glucose uptake and i... | NEW | Summary: ISM1 functions as an adipokine (hormone secreted by adipose tissue) that regulates glucose homeostasis through PI3K-Akt signaling independent of insulin receptors. Reason: ISM1 was identified as a novel adipokine that enhances glucose uptake in adipocytes and skeletal muscle and improves glucose tolerance. It activates PI3K-Akt signaling independently of insulin/IGF receptors, demonstrating hormone-like activity. Supporting Evidence: file:human/ISM1/ISM1-deep-research-falcon.md ISM1 increases glucose uptake in adipocytes and skeletal muscle, improves glucose tolerance, suppresses hepatic lipogenesis, and stimulates hepatic protein synthesis via PI3K-Akt signaling distinct from insulin/IGF receptors file:human/ISM1/ISM1-deep-research-falcon.md Phosphoproteomic mapping shows ~53% overlap with insulin but hundreds of unique phospho-events, including translational control and muscle function nodes PMID:34348115 Epub 2021 Aug 3. Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. |
| GO:0007229 integrin-mediated signaling pathway | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:24464222 Although alphavbeta5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. file:human/ISM1/ISM1-deep-research-falcon.md ISM1 binds integrin alpha8beta1 on mesenchyme, activates FAK/Akt/ERK, promotes N-cadherin expression and aggregation. |
| GO:0046326 positive regulation of D-glucose import across plasma membrane | NAS | NEW | Summary: ISM1 is a secreted hormone that increases glucose uptake in adipocytes and skeletal muscle; it acts on glucose import as an upstream positive regulator, not as a transporter. Reason: Core function term not present in existing_annotations. This row originally proposed GO:0046323 (D-glucose import), which is obsolete in the GO release 2026-07-26 with replaced_by GO:0098708 D-glucose import across plasma membrane. That replacement would assert that ISM1 itself moves glucose, which a secreted signalling protein does not; GO:0046326 positive regulation of D-glucose import across plasma membrane is the correct frame for a hormone that stimulates uptake. Supporting Evidence: file:human/ISM1/ISM1-deep-research-falcon.md ISM1 increases glucose uptake in adipocytes and skeletal muscle, improves glucose tolerance, suppresses hepatic lipogenesis, and stimulates hepatic protein synthesis via PI3K-Akt signaling distinct from insulin/IGF receptors file:human/ISM1/ISM1-deep-research-falcon.md Phosphoproteomic mapping shows ~53% overlap with insulin but hundreds of unique phospho-events, including translational control and muscle function nodes. |
| GO:0019899 enzyme binding | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:24464222 we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (Kd=8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. |
| GO:0005739 mitochondrion | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:24464222 we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (Kd=8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. |
Loading supporting content…
Download this section (compressed HTML)Q: What is the definitive receptor for ISM1's adipokine activity in metabolic tissues? Recent structural work (2025) raised questions about whether purified ISM1 directly activates Akt in adipocytes or requires co-factors.
Q: Does ISM1 have direct enzymatic activity or is it purely a signaling ligand?
Q: What is the relationship between soluble vs matrix-bound ISM1 in determining pro-survival vs pro-apoptotic outcomes?
Experiment: Identify the adipocyte receptor for ISM1 using cross-linking mass spectrometry with highly purified recombinant protein
Hypothesis: ISM1 binds a specific cell-surface receptor on adipocytes that mediates PI3K-Akt activation independent of insulin receptor
Experiment: Compare ISM1 knockout with receptor knockout phenotypes in metabolic tissues
Hypothesis: ISM1 and its metabolic receptor have overlapping phenotypes in glucose homeostasis
Experiment: Structure-function analysis of AMOP domain mutants on integrin binding specificity
Hypothesis: Specific residues in the AMOP domain determine selectivity between alphaVbeta5 and alpha8beta1 integrins
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)