ISM2

Gene Description

ISM2 encodes isthmin-2, a secreted glycoprotein (571 AA) belonging to the isthmin family. The protein contains two characteristic domains: a TSP type-1 repeat (thrombospondin type-1, residues 327-371) and an AMOP domain (adhesion-associated domain shared by MUC4 and other proteins, residues 396-559). ISM2 is synthesized as a precursor with a signal peptide (residues 1-26) that is cleaved to produce the mature secreted protein (residues 27-571). The protein undergoes N-linked glycosylation at three sites (Asn-117, Asn-300, Asn-392) and contains three conserved disulfide bonds in the TSP-1 domain. ISM2 shows high expression in placenta and moderate expression in multiple tissues including pancreas, kidney, heart, liver, lung, brain, and skeletal muscle. Expression data indicate that ISM2 expression in humans is almost specific to the placenta (Martinez et al. 2020, PMID:33088937), with detection in trophoblastic cells by immunohistochemistry and in maternal serum by ELISA; serum ISM2 is significantly decreased in preeclampsia and the protein is overexpressed in choriocarcinoma, leading the authors to propose an angiogenic function. The AMOP domains of ISM1 and ISM2 contain a KGD motif (an integrin αIIbβ3-binding sequence found in known antagonists of platelet aggregation), and ISM2 additionally has a WSRL motif reported to be associated with autophagy induction (Shakhawat et al. 2022, PMID:36611811); these motif-based hypotheses remain to be experimentally validated for ISM2 itself. ISM2 has also been identified as a plasma biomarker decreased in ectopic pregnancy (Beer et al. 2023, PMID:37715129) and is downregulated in the villous core stroma of SARS-CoV-2-infected placentas (Stylianou et al. 2024, PMID:38322491). The TSP-1 domain is known in other proteins to mediate protein-protein and protein-carbohydrate interactions, while the AMOP domain is found in adhesion proteins and mucins. ISM2 interacts with SCN3B (sodium channel beta-3 subunit). While the precise molecular function of ISM2 remains to be fully elucidated, its domain structure and secreted nature suggest roles in cell adhesion, extracellular matrix interactions, or signaling.

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: ISM2 is a secreted protein, as indicated by the presence of a signal peptide (residues 1-26) that targets the protein for secretion. The mature protein (residues 27-571) functions in the extracellular region. [file:human/ISM2/ISM2-uniprot.txt, "SUBCELLULAR LOCATION: Secreted"; "SIGNAL 1..26"; "CHAIN 27..571"] Supporting Evidence: UniProt:Q6H9L7 SUBCELLULAR LOCATION: Secreted {ECO:0000305}. file:human/ISM2/ISM2-deep-research-perplexity.md Isthmin-2 (ISM2), encoded by the ISM2 gene located on human chromosome 14q24.3, is a secreted protein of approximately 63.9 kilodaltons comprising 571 amino acid residues PMID:36611811 Isthmin (ISM) is a secreted protein that was first detected through an unbiased screening for secreted proteins in Xenopus embryos and initially named Xenopus Isthmin (xIsm). The ISM protein family has two members, namely ISM1 (~60 kDa) and ISM2 (~63.9 kDa). Both of these proteins contain a hydrophobic signal peptide at the N-terminus along with a centrally positioned thrombospondin type 1 repeat (TSR1) domain. PMID:33088937 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.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: ISM2 physically interacts with SCN3B (sodium channel beta-3 subunit) as documented in UniProt and supported by a large-scale human binary protein interactome study. The TSP-1 domain in ISM2 is known to mediate protein-protein interactions. However, "protein binding" is a very general term that doesn't provide informative functional annotation about what ISM2 actually does. More specific molecular function terms would be preferable once the binding function is better characterized. Reason: UniProt curates multiple experimental interaction reports with SCN3B; however, the term is too generic to represent a core molecular function and is retained only as non-core. Supporting Evidence: UniProt:Q6H9L7 -!- INTERACTION: Q6H9L7; Q9NY72: SCN3B; NbExp=3; IntAct=EBI-17249161, EBI-17247926; -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305} PMID:32296183 A reference map of the human binary protein interactome.

Core Functions

ISM2 is a secreted glycoprotein containing a thrombospondin type-1 repeat (TSR1) and an AMOP domain, both of which are found in adhesion and extracellular matrix proteins. The protein is secreted into the extracellular region where it likely participates in cell-matrix or cell-cell interactions. ISM2 interacts with SCN3B (sodium channel beta-3 subunit), suggesting a potential role in modulating sodium channel function or localization. The TSR1 domain typically mediates protein-protein and protein-carbohydrate interactions and is found in several anti-angiogenic proteins; the AMOP domain is characteristic of adhesion proteins and mucins and contains a KGD integrin-binding motif in ISM2. ISM2 shows high placental expression and broad tissue distribution, including the nucleus accumbens, suggesting roles in placental biology, tissue development, or angiogenesis modulation. Note on molecular_function: the only experimentally documented MF for ISM2 is generic protein binding (interaction with SCN3B), which CLAUDE.md flags as uninformative; per reviewer feedback on PR #773 the molecular_function slot is intentionally left unspecified here, with extracellular matrix binding / heparin binding / integrin binding all as plausible candidates pending direct biochemical validation.

Cellular Locations:

extracellular region

Supporting Evidence:

file:human/ISM2/ISM2-uniprot.txt
Secreted protein with TSP type-1 domain (327-371) and AMOP domain (396-559). Interacts with SCN3B. Belongs to the isthmin family. Expressed at high levels in placenta and moderate levels in multiple tissues.
PMID:33088937
Expression data indicated that ISM2 expression in humans is almost specific to the placenta
PMID:36611811
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

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Perplexity

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