Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.
A reference map of the human binary protein interactome.
UniProt record for ISM2 (Q6H9L7)
Deep research on ISM2 function
Falcon deep research on ISM2 function (Edison Scientific Literature)
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ISM2 is a secreted ~63.9 kDa isthmin-family protein with an N-terminal signal peptide, a central thrombospondin type-1 repeat (TSR1), and a C-terminal AMOP domain; the strongest 2023-2024 experimental evidence positions ISM2 as a placental marker dysregulated in pregnancy pathologies (preeclampsia, ectopic pregnancy, placenta accreta spectrum, SARS-CoV-2 placentas) rather than as a protein with resolved receptor-ligand biochemistry.
"Most supported statements (direct evidence): 1. Secreted/extracellular protein: ISM2 has a secreted-protein architecture (signal peptide, TSR1 and AMOP domains) and is detected in circulation/plasma-derived compartments in pregnancy studies. 2. Placental association: ISM2 is repeatedly treated as a placental marker and is measurable in maternal serum; it is downregulated in preeclampsia serum and in SARS-CoV-2 placental villous core stroma."
Isthmin 2 is decreased in preeclampsia and highly expressed in choriocarcinoma.
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ISM2 expression in humans is almost specific to the placenta; ISM1 and ISM2 are secreted proteins with N-terminal signal peptides and TSR1+AMOP domain architecture (ISM2 ~63.9 kDa).
"In the human genome, there are two isthmin genes [isthmin 1 (ISM1) and isthmin 2 (ISM2)], both of which encode secreted proteins that exhibit signal peptides, as well as thrombospondin-1 (TSR1) and Adhesion-associated domain in MUC4 and Other Proteins (AMOP) domains. While the ISM1 gene encodes for a protein of ~50 kDa, the ISM2 gene encodes for a protein of ~63.9 kDa"
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Serum ISM2 was decreased in preeclampsia compared with normotensive controls (P = 0.036) and was confirmed by immunohistochemistry in placental trophoblastic cells; ISM2 was overexpressed in choriocarcinoma. Authors interpret these data as consistent with an angiogenic function for ISM2.
"Circulating ISM2 was only statistically significant decreased in women with preeclampsia compared with the control group ... We observed strong (3+) and diffuse positivity in choriocarcinoma ... Taken together, our results suggest an angiogenic function for ISM2."
Isthmin-A Multifaceted Protein Family.
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ISM2 belongs to a family of secreted proteins with TSR1 and AMOP extracellular-protein modules. AMOP of ISM1/ISM2 contains a KGD motif reported to bind integrin αIIbβ3 (a platelet-aggregation antagonist motif). ISM2 additionally contains a WSRL motif in its AMOP domain reported to be involved in autophagy induction. These motif-level claims are domain/sequence-based and have not been validated directly in ISM2-focused biochemical assays.
"AMOP-containing proteins have conserved cysteine (C) residues, while AMOP in both ISM1 and ISM2 also possesses a KGD motif that binds to the integrin αIIbβ3 present in the multiple antagonists of platelet aggregation and is engaged in the integrin-mediated cellular adhesion and tumour metastasis ... Additionally, the AMOP domain in ISM2 also has an WSRL motif that is known to be involved in autophagy induction"
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The role of ISM2 in angiogenesis remains elusive but TSR1-containing proteins are commonly anti-angiogenic; ISM2 contains a WSPW motif in TSR1 that is conserved in several anti-angiogenic proteins and has been reported to mediate inhibition of EC angiogenesis in TSP family contexts.
"At present, the role of ISM2 in angiogenesis still remains elusive, while it is not surprising that it also contains the TSR1 domain, which has been observed in multiple anti-angiogenic proteins ... ISM2 has a WSPW motif that is found to be conserved in ADAMTS12, SBSPON ... It is noteworthy that this heparin-binding motif WSPW in the TSR domain was reported to mediate the inhibition of angiogenesis of ECs"
Identification and verification of plasma protein biomarkers that accurately identify an ectopic pregnancy.
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ISM2 is a placenta/pregnancy-associated plasma protein that was decreased in ectopic pregnancy relative to intrauterine pregnancy and early pregnancy loss (verification cohort AUC = 0.941, P < 0.0001; discovery cohort AUC = 0.775, P = 0.002). Supports ISM2 as a placentally derived secreted protein detectable in maternal circulation.
"ISM2Isthmin-20.7750.0800.6190.9320.002 ... ISM20.9410.0290.88510.9974< 0.0001"
Whole transcriptome profiling of placental pathobiology in SARS-CoV-2 pregnancies identifies placental dysfunction signatures.
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ISM2 is downregulated in the villous core stromal compartment of
SARS-CoV-2-infected placentas relative to controls, consistent with
the protein's known reduction in preeclampsia. Supports a placental
stromal expression pattern responsive to inflammatory/infectious
insult.
"Additionally, the villous core stromal compartment had decreased levels of Isthmin‐2 (ISM2), a placental marker that is downregulated with preeclampsia.
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Circulating microparticle proteins predict pregnancies complicated by placenta accreta spectrum.
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ISM2 is the only circulating microparticle protein (CMP) common to
both the second-trimester (mean AUC 0.83) and third-trimester (mean
AUC 0.78) plasma classifier panels for placenta accreta spectrum
(PAS). The authors interpret this as consistent with ISM2's
placental enrichment, its overexpression in choriocarcinoma, and
proposed cell adhesion / angiogenesis functions for the isthmin
family — making it a candidate maternal-circulation biomarker that
tracks aberrant trophoblast invasion.
"ISM2 was the only protein common to both the second and third trimester panels. Isthmins, including ISM2, represent a family of secreted proteins with diverse functions including cell adhesion and angiogenesis. ISM2 is expressed at high levels in the placenta and is overexpressed in cases of choriocarcinoma, consistent with the invasive nature of PAS
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The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration.
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In SH-SY5Y neuroblastoma cells, sAPPα (soluble amyloid precursor
protein α) treatment significantly up-regulates ISM2 expression at
the mRNA level (validated by qPCR), suggesting a possible — but
experimentally unvalidated — neuronal role for ISM2 downstream of
non-amyloidogenic APP processing. ISM2 is also documented as highly
expressed in the nucleus accumbens, supporting potential neural
function beyond the placental context.
"our cellular in vitro model shows that sAPPα significantly up-regulated ISM2 expression (Figure 4f) suggesting a possible role in neuronal context. Interestingly, ISM2 is mainly expressed in the placenta and has been associated with preeclampsia and choriocarcinoma [185]. However, multiple transcriptomic analyses revealed that ISM2 is also highly expressed in the brain, in particular in the nucleus accumbens
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