NMRK2 (also known as ITGB1BP3, NRK2, or muscle integrin-binding protein/MIBP) is the muscle-enriched paralogue of nicotinamide riboside kinase. As an enzyme it is a cytosolic ATP-dependent kinase of the uridine-kinase (NRK) subfamily that phosphorylates the NAD+ precursor nicotinamide riboside (NR) to nicotinamide mononucleotide (NMN), and nicotinic acid riboside (NaR) to nicotinic acid mononucleotide (NaMN), thereby feeding a Preiss-Handler- independent salvage branch of NAD+ biosynthesis; it can also phosphorylate the cytotoxic nucleoside tiazofurin. Independently of its catalytic activity, the same protein was characterized as a muscle-specific beta-1 integrin-binding protein: it binds ITGB1 (alone or as part of the alpha7-beta1 integrin), reduces cell adhesion to laminin and laminin matrix deposition, modulates paxillin levels and phosphorylation, and influences terminal myogenic differentiation. Expression is strongly enriched in skeletal and cardiac muscle, and the gene is notably induced in muscle stress and heart failure.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) inference of cytoplasmic localization. NMRK2 is a soluble cytosolic metabolic enzyme, so this is correct but non-specific; the more precise GO:0005829 cytosol is also annotated. Reason: Correct compartment but a broad parent of the more informative cytosol annotation. |
| GO:0050262 ribosylnicotinamide kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Nicotinamide riboside kinase activity (EC 2.7.1.22) is the core molecular function of NMRK2, supported by direct experiment and conserved across the NRK subfamily. IBA inference is well founded. |
| GO:0061769 nicotinate riboside kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: NMRK2 also phosphorylates nicotinic acid riboside (EC 2.7.1.173), demonstrated biochemically. IBA inference is consistent with the direct evidence. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: Cytosolic localization is consistent with a soluble NAD-salvage kinase and with the Reactome TAS cytosol annotations. Correct location. |
| GO:0050262 ribosylnicotinamide kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Rule-based (ARBA, mapped from EC 2.7.1.22 / RHEA:14017) assignment of the same core kinase activity that is established experimentally. Correct; redundant with the EXP annotations but supports the core molecular function. |
| GO:0061769 nicotinate riboside kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Rule-based (ARBA, mapped from EC 2.7.1.173 / RHEA:25568) assignment of the nicotinate riboside kinase activity, which is also experimentally supported. Correct; redundant but valid. |
| GO:1901847 nicotinate metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: NMRK2 phosphorylates nicotinic acid riboside within nicotinate/NAD metabolism, so nicotinate metabolic process is correct but a broad parent of the more informative NAD+ salvage-biosynthesis terms. Reason: Correct but general; NAD+ biosynthetic process via the salvage pathway is the more specific process. |
| GO:0005515 protein binding | IPI PMID:12809483 ST7 is a novel low-density lipoprotein receptor-related prot... | MARK AS OVER ANNOTATED | Summary: IntAct IPI from a yeast two-hybrid study in which the cytoplasmic tail of LRP12/ST7 (Q9Y561) was found to interact with muscle integrin-binding protein (MIBP/NMRK2). The interaction is real, but bare "protein binding" is uninformative about NMRK2's function. The biologically meaningful binding activity of this protein is integrin binding (GO:0005178), captured in core_functions. Reason: Uninformative generic binding term; retained per policy for an experimental IPI, but a specific binding MF (integrin binding) is preferred. |
| GO:1901847 nicotinate metabolic process | TAS Reactome:R-HSA-196807 | KEEP AS NON CORE | Summary: Reactome TAS placing NMRK2 in nicotinate metabolism. Correct but a broad parent of the specific NAD+ salvage-biosynthesis process. Reason: Correct but general parent process; NAD+ salvage biosynthesis is more specific. |
| GO:0009435 NAD+ biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: NMRK2 supplies NMN/NaMN to NAD+ biosynthesis via the NR/NaR salvage route (UniPathway UPA00253). This is a core biological process for the gene. The more specific term GO:0034355 (NAD+ biosynthesis via the salvage pathway) better captures the salvage branch. |
| GO:0050262 ribosylnicotinamide kinase activity | EXP PMID:15137942 Discoveries of nicotinamide riboside as a nutrient and conse... | ACCEPT | Summary: Experimental identification of human nicotinamide riboside kinase activity (Bieganowski & Brenner 2004), establishing NMRK2 as a specific NR kinase in the Preiss-Handler-independent NAD+ route. This is the core catalytic function. |
| GO:0050262 ribosylnicotinamide kinase activity | EXP PMID:17914902 Nicotinamide riboside kinase structures reveal new pathways ... | ACCEPT | Summary: Experimental (kinetic + structure-guided) confirmation of NMRK2 nicotinamide riboside kinase activity, including active-site residues essential for human Nrk2 activity in vivo. Core catalytic function. |
| GO:0061769 nicotinate riboside kinase activity | EXP PMID:15137942 Discoveries of nicotinamide riboside as a nutrient and conse... | ACCEPT | Summary: Experimental evidence that human NRK enzymes phosphorylate nicotinic acid riboside (EC 2.7.1.173), a second catalytic activity of NMRK2. |
| GO:0061769 nicotinate riboside kinase activity | EXP PMID:17914902 Nicotinamide riboside kinase structures reveal new pathways ... | ACCEPT | Summary: Kinetic characterization (Tempel et al. 2007) showing NMRK2 phosphorylates nicotinic acid riboside (KM=0.063 mM with ATP), confirming EC 2.7.1.173. Second core catalytic activity. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: Isolated HPA immunofluorescence localization to the nucleoplasm. NMRK2 is a small (~26 kDa) soluble cytosolic NAD-salvage kinase with no known nuclear function, NLS, or literature support for nuclear activity; small proteins can passively equilibrate into the nucleus and antibody-based IF can over-call nuclear signal. Retained (experimental IDA, not removed) but treated as an over-annotation relative to the established cytosolic role. Reason: Single HPA IF observation with no functional or literature corroboration for a nuclear role; core localization is cytosolic. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8869607 | ACCEPT | Summary: Reactome TAS cytosol annotation for the NMRK2-catalyzed NaR->NAMN reaction. Correct core localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8869627 | ACCEPT | Summary: Reactome TAS cytosol annotation for the NMRK2-catalyzed NR->NMN reaction. Correct core localization. |
| GO:0034355 NAD+ biosynthetic process via the salvage pathway | EXP PMID:15137942 Discoveries of nicotinamide riboside as a nutrient and conse... | NEW | Summary: Proposed new annotation capturing the specific salvage branch: NMRK2 phosphorylates NR/NaR to NMN/NaMN, feeding NAD+ biosynthesis via the salvage pathway rather than de novo synthesis. More informative than the existing broad NAD+ biosynthetic process and nicotinate metabolic process annotations. |
| GO:0005178 integrin binding | IPI PMID:12941630 The muscle integrin binding protein (MIBP) interacts with al... | NEW | Summary: Proposed new annotation. NMRK2/MIBP binds integrin beta-1 (ITGB1), alone or as part of the alpha7-beta1 integrin, and regulates cell adhesion and laminin matrix deposition (UniProt SUBUNIT; Li et al. 1999, 2003). GOA currently carries only the uninformative "protein binding" term for this protein; integrin binding is the specific, biologically meaningful MF for the adhesion-related role. |
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Download this section (compressed HTML)Q: Is the integrin-binding/adhesion-modulating activity of NMRK2 (MIBP) dependent on or independent of its nicotinamide riboside kinase catalytic activity, and does one activity regulate the other in muscle?
Q: Given strong induction of NMRK2 in cardiac/skeletal muscle stress and heart failure, does its NR-salvage activity provide a physiologically important NAD+ source under muscle stress relative to NMRK1 and NAMPT?
Experiment: Test catalytically dead NMRK2 (D35A or E100A) for retention of ITGB1 binding and adhesion/myogenesis phenotypes to separate the kinase and integrin- binding functions.
Experiment: Quantify NAD+/NMN flux through the NR and NaR salvage branch in NMRK2-depleted versus NMRK1-depleted muscle cells under basal and stress conditions.
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