INSIG2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005515 protein binding	IPI PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	MODIFY	Summary: Sterol-dependent binding of INSIG2 to SCAP (UniProtKB:P97260), the interaction that holds SCAP-SREBP in the ER. Reason: The interaction is real and is the core mechanism of this protein, but protein binding is uninformative. Binding to sterol-loaded SCAP prevents COPII from engaging SCAP and keeps SCAP-SREBP in the ER, which is what GO:0140311 protein sequestering activity describes; that term is already supported by IDA rows for this gene and by GO-CAM 6205c24300000880. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Proposed replacements: protein sequestering activity Supporting Evidence: PMID:12242332 insig-2 binds to the SCAP/SREBP-2 complex only in the presence of sterols
GO:0005515 protein binding	IPI PMID:17428920 Sterol-regulated transport of SREBPs from endoplasmic reticu...	MODIFY	Summary: Sterol-dependent binding of INSIG2 to SCAP (UniProtKB:Q12770), the interaction that holds SCAP-SREBP in the ER. Reason: The interaction is real and is the core mechanism of this protein, but protein binding is uninformative. Binding to sterol-loaded SCAP prevents COPII from engaging SCAP and keeps SCAP-SREBP in the ER, which is what GO:0140311 protein sequestering activity describes; that term is already supported by IDA rows for this gene and by GO-CAM 6205c24300000880. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Proposed replacements: protein sequestering activity Supporting Evidence: PMID:17428920 Here, we show that oxysterols act by binding to Insigs, causing Insigs to bind to Scap. PMID:17428920 Mutational analysis of the six transmembrane helices of Insigs reveals that the third and fourth are important for Insig's binding to oxysterols and to Scap.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q99942. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:25416956 high-quality human binary protein-protein interactions
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:O14524-2. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:O60883. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P11912. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P15151. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P15941-11. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P16471. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P25942. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P38484. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P41181. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P43628. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:P48165. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q13323. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q13520. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q13571. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q13586. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q15125. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q3ZAQ7. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q4KMG9. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q5JX71. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q7Z5P4. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q7Z7G2. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q8N4V1. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q8NBJ4. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q8TAF8. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q8TB40. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q8TDT2. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q8TED1. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q8TF71. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q96B21. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q96BA8. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q96Q45-2. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q99437. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q99942. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q9BQA9. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q9NUH8. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q9NY72. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG2 with UniProtKB:Q9Y320. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG1 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	MODIFY	Summary: INSIG2 is an ER-resident protein. Reason: Correct but less specific than the evidence: INSIGs are six-transmembrane polytopic proteins of the ER membrane, and the gene already carries GO:0005789 endoplasmic reticulum membrane (IDA, IEA, TAS rows). The ER-membrane term is a part_of descendant and is what the GO-CAM model uses. Judged identically in the INSIG1 review (shared PAINT node / paralog function). For the IBA row, the node (PTN000393022) is sound; only the term granularity is refined. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000393022 SUPPORTS TRANSFER Ancestral INSIG-family node; ER residence is conserved. Only the granularity (ER vs ER membrane) is refined. SGD:S000001175 SUPPORTS TRANSFER Experimental ER localization of an extant INSIG-family member grounds the node; consistent with an integral ER membrane protein. UniProtKB:O15503 SUPPORTS TRANSFER Experimental ER localization of an extant INSIG-family member grounds the node; consistent with an integral ER membrane protein. UniProtKB:Q9Y5U4 SUPPORTS TRANSFER Experimental ER localization of an extant INSIG-family member grounds the node; consistent with an integral ER membrane protein. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:12242332 Insig-1 and -2 are both polytopic membrane proteins of the ER. file:human/INSIG2/INSIG2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005783 endoplasmic reticulum	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	MODIFY	Summary: INSIG2 is an ER-resident protein. Reason: Correct but less specific than the evidence: INSIGs are six-transmembrane polytopic proteins of the ER membrane, and the gene already carries GO:0005789 endoplasmic reticulum membrane (IDA, IEA, TAS rows). The ER-membrane term is a part_of descendant and is what the GO-CAM model uses. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:32322062 SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. file:human/INSIG2/INSIG2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	EXP PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	ACCEPT	Summary: INSIG2 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 Immunofluorescence studies of cells overexpressing epitope-tagged versions of both proteins show an ER distribution with no apparent change in the presence of sterols PMID:12242332 Insig-1 and -2 are both polytopic membrane proteins of the ER.
GO:0005789 endoplasmic reticulum membrane	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG2 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:32322062 SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: INSIG2 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: file:human/INSIG2/INSIG2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	ACCEPT	Summary: INSIG2 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-NUL-2317526	ACCEPT	Summary: INSIG2 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: Reactome:R-NUL-2317526 These interactions retain SCAP:SREBP1A/1C/2 in the endoplasmic reticulum.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-NUL-2317528	ACCEPT	Summary: INSIG2 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: Reactome:R-NUL-2317528 This interaction retains the SREBP2:SCAP:INSIG:oxysterol complex in the endoplasmic reticulum.
GO:0006357 regulation of transcription by RNA polymerase II	NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	MARK AS OVER ANNOTATED	Summary: Regulation of RNA polymerase II transcription inferred from the effect of INSIGs on SREBP processing. Reason: INSIGs are ER membrane proteins with no nuclear role. They change SREBP target-gene transcription only indirectly, by holding SCAP-SREBP in the ER and preventing proteolytic release of the SREBP transcription factor domain. That upstream effect is captured by GO:0036316 and GO:0032933; a transcription-regulation process term overstates the participation. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis.
GO:0006695 cholesterol biosynthetic process	IBA GO_REF:0000033	MODIFY	Summary: Annotated to cholesterol biosynthetic process; INSIGs restrain, rather than carry out, cholesterol synthesis. Reason: INSIGs perform no step of cholesterol synthesis or metabolism. They lower it by retaining SCAP-SREBP in the ER (so less SREBP-driven transcription of sterol-synthesis genes) and by adapting HMGCR to ER-associated degradation. The sound essence is regulatory, with a negative sign: GO:0045541 negative regulation of cholesterol biosynthetic process. For the IBA row, the node placement (PTN001033847, vertebrate INSIGs) is not disputed, only the relation of the protein to the process. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1916289 SOURCE WEAK OR INFERRED Mouse knockout genetic evidence (IGI acts_upstream_of_or_within per QuickGO) shows necessity for normal sterol control, not that INSIG performs a biosynthetic step. MGI:MGI:1920249 SOURCE WEAK OR INFERRED Mouse knockout genetic evidence (IGI acts_upstream_of_or_within per QuickGO) shows necessity for normal sterol control, not that INSIG performs a biosynthetic step. PANTHER:PTN001033847 SUPPORTS TRANSFER Vertebrate INSIG1/INSIG2 node; the target is inside the clade and the paralogs share the function. The issue is the relation to the process (regulator, not participant), not node placement. UniProtKB:O15503 SUPPORTS SOURCE BUT NOT TARGET Human INSIG experimental row for this term; the biology supports negative regulation of cholesterol synthesis rather than participation. UniProtKB:Q9Y5U4 SUPPORTS SOURCE BUT NOT TARGET Human INSIG experimental row for this term; the biology supports negative regulation of cholesterol synthesis rather than participation. Proposed replacements: negative regulation of cholesterol biosynthetic process Supporting Evidence: PMID:12242332 By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0006695 cholesterol biosynthetic process	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	MODIFY	Summary: Annotated to cholesterol biosynthetic process; INSIGs restrain, rather than carry out, cholesterol synthesis. Reason: INSIGs perform no step of cholesterol synthesis or metabolism. They lower it by retaining SCAP-SREBP in the ER (so less SREBP-driven transcription of sterol-synthesis genes) and by adapting HMGCR to ER-associated degradation. The sound essence is regulatory, with a negative sign: GO:0045541 negative regulation of cholesterol biosynthetic process. PMID:32322062 shows that PCK1 phosphorylation of INSIG lowers sterol binding and increases lipogenesis, which again places INSIG as a negative regulator. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Proposed replacements: negative regulation of cholesterol biosynthetic process Supporting Evidence: PMID:32322062 This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0008142 oxysterol binding	IDA PMID:17428920 Sterol-regulated transport of SREBPs from endoplasmic reticu...	ACCEPT	Summary: INSIG2 binds oxysterols such as 25-hydroxycholesterol, which triggers binding to SCAP. Reason: Core activity. Oxysterols act by binding to Insigs (direct binding assays, TM3/TM4 mutants), and a cryo-EM structure of human SCAP-INSIG2 shows 25-hydroxycholesterol bound between SCAP and INSIG TM3/TM4. Accepted in both paralog reviews. Supporting Evidence: PMID:17428920 Here, we show that oxysterols act by binding to Insigs, causing Insigs to bind to Scap. PMID:17428920 These studies define Insigs as oxysterol-binding proteins, explaining the long-known ability of oxysterols to inhibit cholesterol synthesis in animal cells. PMID:33446483 A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. PMID:17428920 Mutational analysis of the six transmembrane helices of Insigs reveals that the third and fourth are important for Insig's binding to oxysterols and to Scap.
GO:0008142 oxysterol binding	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG2 binds oxysterols such as 25-hydroxycholesterol, which triggers binding to SCAP. Reason: Core activity. Oxysterols act by binding to Insigs (direct binding assays, TM3/TM4 mutants), and a cryo-EM structure of human SCAP-INSIG2 shows 25-hydroxycholesterol bound between SCAP and INSIG TM3/TM4. Accepted in both paralog reviews. Supporting Evidence: PMID:32322062 This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus PMID:33446483 A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. PMID:17428920 Mutational analysis of the six transmembrane helices of Insigs reveals that the third and fourth are important for Insig's binding to oxysterols and to Scap.
GO:0008203 cholesterol metabolic process	NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	MODIFY	Summary: Annotated to cholesterol metabolic process; INSIGs restrain, rather than carry out, cholesterol synthesis. Reason: INSIGs perform no step of cholesterol synthesis or metabolism. They lower it by retaining SCAP-SREBP in the ER (so less SREBP-driven transcription of sterol-synthesis genes) and by adapting HMGCR to ER-associated degradation. The sound essence is regulatory, with a negative sign: GO:0045541 negative regulation of cholesterol biosynthetic process. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Proposed replacements: negative regulation of cholesterol biosynthetic process Supporting Evidence: PMID:12242332 By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0032868 response to insulin	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to insulin, based on insulin-regulated expression of the INSIG genes. Reason: Insulin changes the abundance of INSIG transcripts: INSIG1 (the 'insulin-induced gene', rat CL-6) is induced, and the liver-specific Insig-2a transcript is repressed. That is regulation of the gene by insulin, not a function the INSIG protein performs in an insulin response; the opposite signs in the two paralogs also argue that no shared, inherited protein function is involved. The IEA is an ortholog transfer of the same expression-based claim. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:9268630 Rat CL-6 is the most highly insulin-induced gene in a liver cell line PMID:12624180 Insig-2a is the predominant transcript in livers of fed animals, and it is selectively down-regulated by insulin.
GO:0032869 cellular response to insulin stimulus	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Response to insulin, based on insulin-regulated expression of the INSIG genes. Reason: Insulin changes the abundance of INSIG transcripts: INSIG1 (the 'insulin-induced gene', rat CL-6) is induced, and the liver-specific Insig-2a transcript is repressed. That is regulation of the gene by insulin, not a function the INSIG protein performs in an insulin response; the opposite signs in the two paralogs also argue that no shared, inherited protein function is involved. The IBA node (PTN001033847) rests on rat Insig1, whose own row for this term is an IEP (expression) annotation, so the propagated claim inherits an expression-pattern observation rather than a functional one. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: PANTHER:PTN001033847 SOURCE WEAK OR INFERRED Node placement covers both paralogs, but its only descendant evidence for this term is an expression-pattern observation. RGD:708457 SOURCE WEAK OR INFERRED Rat Insig1 row for this term is IEP (insulin induction of the transcript), which does not show a protein function in the insulin response. Supporting Evidence: PMID:9268630 Rat CL-6 is the most highly insulin-induced gene in a liver cell line PMID:12624180 Insig-2a is the predominant transcript in livers of fed animals, and it is selectively down-regulated by insulin.
GO:0032933 SREBP signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: INSIG2 is a sterol-sensing component of the SREBP pathway that blocks SCAP-SREBP export when sterols are high. Reason: INSIGs act within the SREBP signaling pathway itself, at its first, sterol-gated step: transport of SCAP-SREBP from the ER to the Golgi. The more specific GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum is accepted as the core process; this pathway-level term still adds context and is kept. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi.
GO:0032933 SREBP signaling pathway	IDA PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	ACCEPT	Summary: INSIG2 is a sterol-sensing component of the SREBP pathway that blocks SCAP-SREBP export when sterols are high. Reason: INSIGs act within the SREBP signaling pathway itself, at its first, sterol-gated step: transport of SCAP-SREBP from the ER to the Golgi. The more specific GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum is accepted as the core process; this pathway-level term still adds context and is kept. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 We demonstrate that insig-2 can also bind the SCAP/SREBP complex and cause its retention in the ER in a sterol-dependent fashion. PMID:12242332 Coexpression of insig-1 or -2 did not affect budding in the absence of sterols (lanes 4 and 6), but it permitted sterols to specifically block SCAP budding without affecting the budding of the G protein of VSV (lanes 5 and 7).
GO:0032933 SREBP signaling pathway	IDA PMID:17428920 Sterol-regulated transport of SREBPs from endoplasmic reticu...	ACCEPT	Summary: INSIG2 is a sterol-sensing component of the SREBP pathway that blocks SCAP-SREBP export when sterols are high. Reason: INSIGs act within the SREBP signaling pathway itself, at its first, sterol-gated step: transport of SCAP-SREBP from the ER to the Golgi. The more specific GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum is accepted as the core process; this pathway-level term still adds context and is kept. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:17428920 Here, we show that oxysterols act by binding to Insigs, causing Insigs to bind to Scap.
GO:0032933 SREBP signaling pathway	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG2 is a sterol-sensing component of the SREBP pathway that blocks SCAP-SREBP export when sterols are high. Reason: INSIGs act within the SREBP signaling pathway itself, at its first, sterol-gated step: transport of SCAP-SREBP from the ER to the Golgi. The more specific GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum is accepted as the core process; this pathway-level term still adds context and is kept. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:32322062 SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum.
GO:0032937 SREBP-SCAP-Insig complex	IBA GO_REF:0000033	ACCEPT	Summary: INSIG2 forms the sterol-induced SREBP-SCAP-Insig complex in the ER membrane. Reason: The complex is defined by INSIG association with SCAP-SREBP and was detected by co-immunoprecipitation and blue native-PAGE. INSIG is a defining subunit. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi.
GO:0032937 SREBP-SCAP-Insig complex	IDA PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	ACCEPT	Summary: INSIG2 forms the sterol-induced SREBP-SCAP-Insig complex in the ER membrane. Reason: The complex is defined by INSIG association with SCAP-SREBP and was detected by co-immunoprecipitation and blue native-PAGE. INSIG is a defining subunit. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 insig-2 binds to the SCAP/SREBP-2 complex only in the presence of sterols
GO:0032937 SREBP-SCAP-Insig complex	NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	ACCEPT	Summary: INSIG2 forms the sterol-induced SREBP-SCAP-Insig complex in the ER membrane. Reason: The complex is defined by INSIG association with SCAP-SREBP and was detected by co-immunoprecipitation and blue native-PAGE. INSIG is a defining subunit. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER PMID:12202038 Sterols induce binding of SCAP to INSIG-1, as determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from the ER.
GO:0033993 response to lipid	IEA GO_REF:0000107	MODIFY	Summary: Response to lipid, transferred from rodent orthologs. Reason: INSIG2 does respond directly to a class of lipids: oxysterol binding induces its binding to SCAP. Response to lipid is correct but broad; the specific, supported term is GO:0036315 cellular response to sterol (INSIG1 carries it by IMP). Proposed replacements: cellular response to sterol Supporting Evidence: PMID:17428920 Here, we show that oxysterols act by binding to Insigs, causing Insigs to bind to Scap. PMID:12242332 insig-2 binds to the SCAP/SREBP-2 complex only in the presence of sterols
GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum	IBA GO_REF:0000033	ACCEPT	Summary: INSIG2 retains the SCAP-SREBP complex in the ER when sterols are present. Reason: Core process. Sterol-induced INSIG binding to SCAP prevents COPII from engaging SCAP's MELADL sorting signal, so SCAP-SREBP stays in the ER and SREBPs are not processed in the Golgi. The IBA node PTN001033847 (vertebrate INSIG1/INSIG2) is well founded on experimental data for both paralogs. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi.
GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum	IDA PMID:15899885 Insig required for sterol-mediated inhibition of Scap/SREBP ...	ACCEPT	Summary: INSIG2 retains the SCAP-SREBP complex in the ER when sterols are present. Reason: Core process. Sterol-induced INSIG binding to SCAP prevents COPII from engaging SCAP's MELADL sorting signal, so SCAP-SREBP stays in the ER and SREBPs are not processed in the Golgi. The cached abstract of PMID:15899885 names Insig-1; the curator's INSIG2 IDA is presumably from the full text. The function is in any case established for INSIG2 (PMID:12242332, vesicle-budding assay), so the row is accepted and deferred to the curator. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:15899885 This in vitro inhibition is dependent on the presence of Insig-1, an ER resident protein that is necessary for sterol-mediated inhibition of Scap/SREBP transport in intact cells. PMID:15899885 addition of cholesterol or 25-hydroxycholesterol to microsomal membranes in vitro blocks Sar1-dependent binding of the Sec23/24 complex to Scap, the SREBP escort protein PMID:12242332 Coexpression of insig-1 or -2 did not affect budding in the absence of sterols (lanes 4 and 6), but it permitted sterols to specifically block SCAP budding without affecting the budding of the G protein of VSV (lanes 5 and 7).
GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG2 retains the SCAP-SREBP complex in the ER when sterols are present. Reason: Core process. Sterol-induced INSIG binding to SCAP prevents COPII from engaging SCAP's MELADL sorting signal, so SCAP-SREBP stays in the ER and SREBPs are not processed in the Golgi. PMID:32322062 is a single-laboratory study, but its IDA for this process agrees with earlier work. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:32322062 This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus
GO:0070542 response to fatty acid	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Response to fatty acid, transferred by Ensembl Compara from rodent Insig2. Reason: No human evidence was found that INSIG2 protein acts in a response to fatty acids. The rodent source is likely expression-level, as with the insulin terms. Unsaturated-fatty-acid effects on Insig stability have been described for INSIG1, not INSIG2. The sterol response is the supported one (see GO:0036315). Supporting Evidence: PMID:12242332 the insig-2 mRNA was expressed constitutively and was not affected by induction of either SREBP
GO:0140311 protein sequestering activity	IDA PMID:15899885 Insig required for sterol-mediated inhibition of Scap/SREBP ...	ACCEPT	Summary: INSIG2 binds sterol-loaded SCAP and sequesters it from COPII, holding SCAP-SREBP in the ER. Reason: Core molecular function. Insig binding makes SCAP's MELADL signal inaccessible to Sec23/24, so SCAP is prevented from entering COPII vesicles. This matches the GO:0140311 definition (binding a protein to stop its localization) and the GO-CAM model 6205c24300000880. The cached abstract names Insig-1 only; the curator's INSIG2 IDA (full text) is retained because INSIG2 performs the same SCAP retention (PMID:12242332). Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:15899885 This in vitro inhibition is dependent on the presence of Insig-1, an ER resident protein that is necessary for sterol-mediated inhibition of Scap/SREBP transport in intact cells. PMID:15899885 addition of cholesterol or 25-hydroxycholesterol to microsomal membranes in vitro blocks Sar1-dependent binding of the Sec23/24 complex to Scap, the SREBP escort protein PMID:12242332 insig-2 binds to the SCAP/SREBP-2 complex only in the presence of sterols PMID:17428919 Cholesterol and oxysterols block COPII binding to MELADL by binding to different intracellular receptors, cholesterol to Scap and oxysterols to Insig.
GO:0140311 protein sequestering activity	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG2 binds sterol-loaded SCAP and sequesters it from COPII, holding SCAP-SREBP in the ER. Reason: Core molecular function. Insig binding makes SCAP's MELADL signal inaccessible to Sec23/24, so SCAP is prevented from entering COPII vesicles. This matches the GO:0140311 definition (binding a protein to stop its localization) and the GO-CAM model 6205c24300000880. Judged identically in the INSIG1 review (shared PAINT node / paralog function). Supporting Evidence: PMID:32322062 This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus PMID:17428919 Cholesterol and oxysterols block COPII binding to MELADL by binding to different intracellular receptors, cholesterol to Scap and oxysterols to Insig.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity	IDA PMID:22143767 Sterol-induced degradation of HMG CoA reductase depends on i...	NEW	Summary: INSIG2 links sterol-loaded HMGCR to the TRC8 ubiquitin ligase for sterol-accelerated ERAD. Reason: Parallels the INSIG1 rows MODIFIED to this term. Both Insigs bind TRC8, and RNAi shows that HMGCR-Trc8 binding is mediated by both Insig-1 and Insig-2. INSIG2 needs the same conserved juxtamembrane Asp for HMGCR degradation, and RNF145 also binds INSIG2. INSIG2 itself bridges the ligase and the substrate, so the adaptor activity is the gene product's own work, not mere necessity. Supporting Evidence: PMID:22143767 both Insig-1 and Insig-2 bind another membrane-bound RING-finger ubiquitin ligase called Trc8 PMID:22143767 The gp78-dependent ubiquitination of reductase is mediated primarily by Insig-1, whereas Trc8-dependent ubiquitination is mediated by both Insig-1 and Insig-2. PMID:16606821 Alanine substitution of the corresponding aspartic acid in Insig-2 produced the same dual defects. PMID:29374057 RNF145 interacts with Insig-1 and -2 proteins and ubiquitinates HMGCR
GO:1901303 negative regulation of cargo loading into COPII-coated vesicle	IDA PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	NEW	Summary: Sterol-loaded INSIG2 specifically blocks incorporation of SCAP into ER-derived transport vesicles. Reason: Mirrors the accepted INSIG1 IMP row (PMID:15899885). In an in vitro budding assay INSIG2 let sterols block SCAP entry into ER-derived vesicles without affecting VSV-G, i.e. it negatively regulates loading of one specific cargo into COPII vesicles. Insig binding makes the SCAP MELADL COPII signal inaccessible. INSIG2 does this itself by binding SCAP, so it passes the participation test. Supporting Evidence: PMID:12242332 Coexpression of insig-1 or -2 did not affect budding in the absence of sterols (lanes 4 and 6), but it permitted sterols to specifically block SCAP budding without affecting the budding of the G protein of VSV (lanes 5 and 7). PMID:17428919 Cholesterol and oxysterols block COPII binding to MELADL by binding to different intracellular receptors, cholesterol to Scap and oxysterols to Insig.

Gene Description

Existing Annotations Review

Core Functions

Sterol-dependent sequestration of SCAP: INSIG2 binds the sterol-sensing domain of sterol-loaded SCAP and keeps the SCAP-SREBP complex in the ER membrane by masking SCAP's COPII sorting signal, which blocks SREBP transport to the Golgi and its activation.

Oxysterol sensing: INSIG2 binds 25-hydroxycholesterol and related oxysterols in a transmembrane pocket formed with TM3/TM4, which drives its association with SCAP.

Substrate adaptor for sterol-accelerated ER-associated degradation: INSIG2 binds the sterol-sensing domain of HMG-CoA reductase and links it to ER ubiquitin ligases (mainly TRC8/RNF139 and RNF145; INSIG2 binds gp78 poorly), lowering cholesterol synthesis.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

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