The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan overview
- Verified identity: DAB2IP (aka AIP1/KIAA1743) is a human RasGAP-family tumor suppressor with scaffold/adaptor functions; literature aligns with UniProt Q5VWQ8, including PH/C2-like features, RasGAP catalytic region, and C-terminal proline-rich segments. The organism is Homo sapiens. Domains and aliases in recent reviews match the UniProt description; no conflicting gene symbols were identified in recent human literature (Jun 2024 review; Mar 2023 primary study) (fania2024anupdateon pages 1-2, miller2023dab2ipisa pages 1-2).
- Collected recent evidence (2023–2024) on function, domains, pathways, localization, regulation, and disease relevance from peer‑reviewed journals and recent preprints, plus one 2025 mini‑review where helpful for domain/regulatory details (URLs provided) (fania2024anupdateon pages 1-2, apollonio2023thetumorsuppressor pages 18-19, fania2024anupdateon pages 2-3, shen2024dab2ipinhibitsglucose pages 15-16, song2025asystematicanalysis pages 8-9, song2025asystematicanalysis pages 21-21, miller2023dab2ipisa pages 1-2).
- Synthesized mechanistic roles, interactors, localization, regulation, and translational implications; created a concise artifact table for quick reference (below).

Table: Compact evidence-based summary of human DAB2IP (UniProt Q5VWQ8) covering identity, domains, functions, interactors, pathways, localization, regulation, and disease relevance with citations to 2023–2024 literature and related sources.

Comprehensive research report: DAB2IP (UniProt Q5VWQ8, Homo sapiens)

1) Key concepts and definitions
- Identity and domain architecture: DAB2IP (Disabled homolog 2‑interacting protein; also AIP1/KIAA1743) is a Ras GTPase‑activating protein (RASGAP) and cytoplasmic adaptor/scaffold that integrates multiple signaling pathways in human cells (Cell Death & Differentiation, 20 Jun 2024; https://doi.org/10.1038/s41418-024-01332-3) (fania2024anupdateon pages 1-2). Domain-wise, DAB2IP contains a RasGAP catalytic region that accelerates Ras‑GTP hydrolysis, PH/C2‑like lipid/membrane‑associated modules, and C-terminal proline‑rich segments (PER/CPR) engaged in protein–protein interactions; multiple isoforms arise from alternative TSS/splicing (Cancers, Apr 2025; https://doi.org/10.3390/cancers17091485; review synthesis in 2024 Cell Death & Differentiation) (song2025asystematicanalysis pages 8-9, fania2024anupdateon pages 1-2).
- Primary biochemical function: As a RasGAP, DAB2IP restrains the RAS–RAF–MEK–ERK pathway by catalyzing RAS‑GTP to RAS‑GDP, and also functions as a scaffold to promote pro‑apoptotic ASK1–JNK signaling and dampen inflammatory/NF‑κB and PI3K–AKT outputs (Cancer Research, 30 Mar 2023; https://doi.org/10.1158/0008-5472.can-22-0370; Cell Death & Differentiation, 20 Jun 2024; https://doi.org/10.1038/s41418-024-01332-3) (miller2023dab2ipisa pages 1-2, fania2024anupdateon pages 1-2).

2) Recent developments and latest research (2023–2024)
- Colon cancer: DAB2IP is a bifunctional tumor suppressor that, when lost, amplifies wild‑type H‑/N‑RAS signaling in KRAS‑mutant colorectal cancers and triggers inflammatory mediator production with macrophage recruitment; early-stage tumors frequently lose DAB2IP via mutation or epigenetic silencing (Cancer Research, 30 Mar 2023; https://doi.org/10.1158/0008-5472.can-22-0370) (miller2023dab2ipisa pages 1-2).
- Hippo/YAP–TAZ and cell contact: DAB2IP levels increase with confluency; depletion in confluent epithelial cells promotes YAP/TAZ nuclear localization and activity, altering cell mechanics (Cancers, 30 Jun 2023; https://doi.org/10.3390/cancers15133379) (apollonio2023thetumorsuppressor pages 18-19).
- Metabolism/HIF‑1α: Under hypoxia in breast cancer cells, DAB2IP interacts via its PER domain with the E3 ligase STUB1 (CHIP) to promote HIF‑1α ubiquitination and degradation, thereby inhibiting glucose uptake, ATP production, and lactate output; loss of the PER domain abrogates these effects (Oncogenesis, Jun 2024; https://doi.org/10.1038/s41389-024-00523-4; Research Square preprint, Jan 2024; https://doi.org/10.21203/rs.3.rs-3825204/v1) (shen2024dab2ipinhibitsglucose pages 15-16).
- Clear cell renal cell carcinoma (ccRCC): DAB2IP stabilizes p27Kip1 by suppressing PI3K/AKT signaling; its C‑terminal proline‑rich region (CPR) is necessary to inhibit AKT phosphorylation and p27 S10 phosphorylation, countering p27 cytosolic sequestration and degradation (Functional & Integrative Genomics, Oct 2023; https://doi.org/10.1007/s10142-023-01255-1) (song2025asystematicanalysis pages 21-21).
- Cross‑pathway integration: A 2024 review synthesizes DAB2IP’s roles across TNFα/NF‑κB, WNT/β‑catenin, PI3K/AKT, JAK/STAT, and MAPK signaling, pro‑apoptotic ASK1/JNK activation, genomic stability via PLK1, and primary cilium stabilization (Cell Death & Differentiation, 20 Jun 2024; https://doi.org/10.1038/s41418-024-01332-3) (fania2024anupdateon pages 1-2, fania2024anupdateon pages 2-3).

3) Current applications and real‑world implementations
- Therapeutic vulnerabilities in KRAS‑mutant CRC: DAB2IP loss drives inflammatory cytokine programs; tumor growth suppression was achieved via macrophage depletion or JAK/TBK1 inhibition to curb mediator expression in preclinical models, pointing to combinatorial strategies in KRAS‑mutant settings (Cancer Research, 30 Mar 2023; https://doi.org/10.1158/0008-5472.can-22-0370) (miller2023dab2ipisa pages 1-2).
- Hippo/YAP–TAZ and epithelial integrity: Cell-density–dependent upregulation of DAB2IP and YAP/TAZ inhibition suggest tissue‑context strategies to restore DAB2IP and restrain oncogenic mechanotransduction in solid tumors (Cancers, 30 Jun 2023; https://doi.org/10.3390/cancers15133379) (apollonio2023thetumorsuppressor pages 18-19).
- Metabolic targeting: Enhancing DAB2IP–STUB1 control of HIF‑1α under hypoxia suggests a route to diminish tumor glycolysis and growth in breast cancer models; domain mapping (PER) provides a structural handle for small‑molecule or peptide design (Oncogenesis, Jun 2024; https://doi.org/10.1038/s41389-024-00523-4; preprint, Jan 2024; https://doi.org/10.21203/rs.3.rs-3825204/v1) (shen2024dab2ipinhibitsglucose pages 15-16).
- Review‑driven proposals: Reactivating/upregulating DAB2IP is proposed to attenuate several oncogenic pathways concurrently in cancer cells and stroma, positioning DAB2IP as a therapeutic reactivation target (Cell Death & Differentiation, 20 Jun 2024; https://doi.org/10.1038/s41418-024-01332-3) (fania2024anupdateon pages 1-2).

4) Expert opinions and analysis from authoritative sources
- 2024 expert review perspective: DAB2IP is a central RasGAP/scaffold whose downregulation in tumors results from promoter methylation, miRNA regulation, and protein interactions; restoring its function may blunt RAS‑dependent mitogenic signaling and multiple parallel oncogenic pathways, including TNFα/NF‑κB, WNT/β‑catenin, PI3K/AKT, and AR signaling (Cell Death & Differentiation, 20 Jun 2024; https://doi.org/10.1038/s41418-024-01332-3) (fania2024anupdateon pages 1-2).
- 2023 primary study viewpoint: In KRAS‑mutant CRC, DAB2IP loss is not redundant with KRAS mutation; instead, it amplifies signaling via activation of wild‑type RAS isoforms and shapes a protumor inflammatory microenvironment, supporting early detection/biomarker development and inflammation‑targeted combinations (Cancer Research, 30 Mar 2023; https://doi.org/10.1158/0008-5472.can-22-0370) (miller2023dab2ipisa pages 1-2).

5) Relevant statistics and recent data
- RAS mutation epidemiology context: Approximately 30% of human tumors carry RAS mutations; KRAS mutations occur in ~40% of colorectal cancers (reported within the 2023 Cancer Research study context) (Cancer Research, 30 Mar 2023; https://doi.org/10.1158/0008-5472.can-22-0370) (miller2023dab2ipisa pages 1-2).
- ccRCC functional data: DAB2IP knockdown increases proliferation and G1/S progression in ccRCC cells; mechanistically, DAB2IP loss increases AKT and p27 S10 phosphorylation, promoting p27 cytosolic sequestration and ubiquitin‑mediated degradation, whereas the DAB2IP CPR region suppresses these events (Functional & Integrative Genomics, Oct 2023; https://doi.org/10.1007/s10142-023-01255-1) (song2025asystematicanalysis pages 21-21).
- Hypoxia/metabolic outputs: Under hypoxia in breast cancer models, deletion of the DAB2IP PER domain abrogates reductions in glucose uptake, ATP, and lactate observed with intact DAB2IP, consistent with a requirement for DAB2IP–STUB1 in HIF‑1α turnover (Oncogenesis, Jun 2024; https://doi.org/10.1038/s41389-024-00523-4; preprint, Jan 2024; https://doi.org/10.21203/rs.3.rs-3825204/v1) (shen2024dab2ipinhibitsglucose pages 15-16).

Focused functional annotation
- Enzymatic activity: RasGAP activity that inactivates RAS to restrain RAF–MEK–ERK signaling; in KRAS‑mutant CRC, DAB2IP loss specifically amplifies signaling via activation of wild‑type RAS isoforms, enhancing effector pathway throughput (Cancer Research, 30 Mar 2023; https://doi.org/10.1158/0008-5472.can-22-0370) (miller2023dab2ipisa pages 1-2).
- Scaffold/adaptor roles: DAB2IP binds TRAF2 and ASK1 to promote pro‑apoptotic JNK activation in TNFα signaling; it interacts with STUB1/CHIP via its PER domain to promote HIF‑1α ubiquitination under hypoxia; with GRP75 it stabilizes wild‑type p53; it affects USP10/ALK turnover and GSK3β/β‑catenin; it coordinates PLK1/HBO1 to support DNA replication and genomic stability (Research Square preprint/Oncogenesis 2024; Cell Death & Differentiation, 20 Jun 2024) (shen2024dab2ipinhibitsglucose pages 15-16, fania2024anupdateon pages 1-2).
- Subcellular localization: Cytoplasmic and membrane‑associated (via PH/C2‑like modules; primary cilium interaction through KIF3A), and nuclear roles in DNA replication via PLK1–HBO1 complexes; cell contact elevates DAB2IP with effects on YAP/TAZ nuclear localization (Cancers, 30 Jun 2023; https://doi.org/10.3390/cancers15133379; Cell Death & Differentiation, 20 Jun 2024) (apollonio2023thetumorsuppressor pages 18-19, fania2024anupdateon pages 1-2, fania2024anupdateon pages 2-3).
- Regulation: Frequently downregulated by promoter methylation and miRNAs; cell‑density/ECM mechanics modulate expression; post‑translational regulation via proteostasis networks (e.g., USP10, STUB1). A 2025 mini‑review summarizes regulatory circuits (epigenetic silencing and ncRNA axes) especially in urological cancers (Cancers, Apr 2025; https://doi.org/10.3390/cancers17091485; plus 2024 review) (song2025asystematicanalysis pages 8-9, fania2024anupdateon pages 1-2, apollonio2023thetumorsuppressor pages 18-19, song2025asystematicanalysis pages 21-21).

Disease and pathway integration
- Colorectal cancer: Early DAB2IP loss cooperates with KRAS mutations by amplifying WT RAS signaling and activating inflammatory programs; macrophage depletion or JAK/TBK1 inhibition reduces tumor growth in models (Cancer Research, 30 Mar 2023; https://doi.org/10.1158/0008-5472.can-22-0370) (miller2023dab2ipisa pages 1-2).
- Prostate and other solid tumors: Broad tumor‑suppressor roles with loss linked to EMT, invasion, resistance, and activation of β‑catenin and YAP/TAZ in epithelial contexts (Cell Death & Differentiation, 20 Jun 2024; Cancers, 30 Jun 2023) (fania2024anupdateon pages 1-2, apollonio2023thetumorsuppressor pages 18-19, fania2024anupdateon pages 7-7).
- Renal cell carcinoma: DAB2IP suppresses PI3K/AKT to stabilize p27, acts as a prognostic marker, and links to therapy responses (Functional & Integrative Genomics, Oct 2023; review synthesis) (song2025asystematicanalysis pages 21-21, song2025asystematicanalysis pages 8-9).
- Breast cancer: DAB2IP restrains HIF‑1α and glucose metabolism under hypoxia through STUB1; its depletion promotes metabolic reprogramming and tumor progression in models (Oncogenesis, Jun 2024; preprint, Jan 2024) (shen2024dab2ipinhibitsglucose pages 15-16).

Verification checklist (mandatory)
- Gene symbol matches protein description: Yes—DAB2IP encodes a RasGAP/scaffold protein referred to as AIP1/DAB2IP in the literature; aligns with UniProt description and aliases (2024 review; 2023 primary) (fania2024anupdateon pages 1-2, miller2023dab2ipisa pages 1-2).
- Organism: Homo sapiens—All cited recent studies examine human DAB2IP or human cancer models and are consistent with the human gene (miller2023dab2ipisa pages 1-2, fania2024anupdateon pages 1-2).
- Domains/family: RasGAP family; PH/C2‑like membrane‑associating features; C‑terminal PER/CPR interaction regions—consistent with UniProt domain annotations and recent literature summaries (song2025asystematicanalysis pages 8-9, fania2024anupdateon pages 1-2).
- Ambiguity: No conflicting gene with the same symbol in human noted in 2023–2024 literature surveyed; scope restricted to DAB2IP/AIP1 per UniProt Q5VWQ8 (fania2024anupdateon pages 1-2, miller2023dab2ipisa pages 1-2).

References (with URLs and publication dates)
- Review: De Florian Fania R., Bellazzo A., Collavin L. An update on the tumor-suppressive functions of the RasGAP protein DAB2IP with focus on therapeutic implications. Cell Death & Differentiation. Published online 20 Jun 2024. URL: https://doi.org/10.1038/s41418-024-01332-3 (fania2024anupdateon pages 1-2, fania2024anupdateon pages 7-7, fania2024anupdateon pages 2-3).
- Primary: Miller A.L. et al. DAB2IP Is a Bifunctional Tumor Suppressor That Regulates Wild-Type RAS and Inflammatory Cascades in KRAS Mutant Colon Cancer. Cancer Research. 30 Mar 2023;83(11):1800–1814. URL: https://doi.org/10.1158/0008-5472.can-22-0370 (miller2023dab2ipisa pages 1-2).
- Mechanotransduction/Hippo: Apollonio M. et al. The Tumor Suppressor DAB2IP Is Regulated by Cell Contact and Contributes to YAP/TAZ Inhibition in Confluent Cells. Cancers. 30 Jun 2023;15(13):3379. URL: https://doi.org/10.3390/cancers15133379 (apollonio2023thetumorsuppressor pages 18-19).
- Metabolism/HIF-1α: Dong H./Shen J. et al. DAB2IP inhibits glucose uptake by modulating HIF‑1α ubiquitination under hypoxia in breast cancer. Oncogenesis. Jun 2024. URL: https://doi.org/10.1038/s41389-024-00523-4; Research Square preprint, 16 Jan 2024. URL: https://doi.org/10.21203/rs.3.rs-3825204/v1 (shen2024dab2ipinhibitsglucose pages 15-16).
- ccRCC function: Zhou J.-c. et al. DAB2IP stabilizes p27Kip1 via suppressing PI3K/AKT signaling in clear cell renal cell carcinoma. Functional & Integrative Genomics. Oct 2023;23(4). URL: https://doi.org/10.1007/s10142-023-01255-1 (song2025asystematicanalysis pages 21-21).
- Urological cancer mini‑review (domains/regulation synthesis): Song H. et al. A Systematic Analysis of Expression and Function of RASGAPs in Urological Cancers. Cancers. Apr 2025;17(9):1485. URL: https://doi.org/10.3390/cancers17091485 (used to complement domain/regulatory notes) (song2025asystematicanalysis pages 8-9, song2025asystematicanalysis pages 21-21).

Conclusion
Human DAB2IP (Q5VWQ8) is a RasGAP and multifunctional scaffold that restrains RAS/MAPK and PI3K/AKT signaling, promotes pro‑apoptotic ASK1–JNK activation, and modulates inflammatory, WNT/β‑catenin, Hippo/YAP–TAZ, and hypoxia/HIF‑1α pathways in context‑dependent ways. It localizes primarily in the cytoplasm and at membranes (including the primary cilium) and exerts nuclear functions in DNA replication control via PLK1/HBO1. DAB2IP is frequently downregulated in cancers via promoter methylation and miRNA mechanisms, associates with aggressive behavior and therapy resistance, and presents opportunities for therapeutic reactivation and pathway‑directed combination treatments, with recent studies underscoring metabolic and inflammatory vulnerabilities in vivo (Jun 2024 review; Mar 2023 Cancer Research; Oct 2023 ccRCC; Jun 2024 Oncogenesis) (fania2024anupdateon pages 1-2, miller2023dab2ipisa pages 1-2, song2025asystematicanalysis pages 21-21, shen2024dab2ipinhibitsglucose pages 15-16).

References

1. (fania2024anupdateon pages 1-2): Rossella De Florian Fania, Arianna Bellazzo, and Licio Collavin. An update on the tumor-suppressive functions of the rasgap protein dab2ip with focus on therapeutic implications. Cell Death and Differentiation, 31:844-854, Jun 2024. URL: https://doi.org/10.1038/s41418-024-01332-3, doi:10.1038/s41418-024-01332-3. This article has 6 citations and is from a domain leading peer-reviewed journal.

2. (miller2023dab2ipisa pages 1-2): Abigail L. Miller, Naiara Perurena, Alycia Gardner, Toshinori Hinoue, Patrick Loi, Peter W. Laird, and Karen Cichowski. Dab2ip is a bifunctional tumor suppressor that regulates wild-type ras and inflammatory cascades in kras mutant colon cancer. Cancer Research, 83:1800-1814, Mar 2023. URL: https://doi.org/10.1158/0008-5472.can-22-0370, doi:10.1158/0008-5472.can-22-0370. This article has 11 citations and is from a highest quality peer-reviewed journal.

3. (apollonio2023thetumorsuppressor pages 18-19): Mattia Apollonio, Arianna Bellazzo, Nicoletta Franco, Silvia Lombardi, Beatrice Senigagliesi, Loredana Casalis, Pietro Parisse, Agnes Thalhammer, Gabriele Baj, Rossella De Florian Fania, Giannino Del Sal, and Licio Collavin. The tumor suppressor dab2ip is regulated by cell contact and contributes to yap/taz inhibition in confluent cells. Cancers, 15:3379, Jun 2023. URL: https://doi.org/10.3390/cancers15133379, doi:10.3390/cancers15133379. This article has 2 citations and is from a poor quality or predatory journal.

4. (fania2024anupdateon pages 2-3): Rossella De Florian Fania, Arianna Bellazzo, and Licio Collavin. An update on the tumor-suppressive functions of the rasgap protein dab2ip with focus on therapeutic implications. Cell Death and Differentiation, 31:844-854, Jun 2024. URL: https://doi.org/10.1038/s41418-024-01332-3, doi:10.1038/s41418-024-01332-3. This article has 6 citations and is from a domain leading peer-reviewed journal.

5. (shen2024dab2ipinhibitsglucose pages 15-16): Jie Shen, Hongliang Dong, Weiyi Jia, Weijian Meng, Rui Zhang, Zhihong Qi, Zhuo Chen, Sophia Xie, Jiang Min, and Liang Liu. Dab2ip inhibits glucose uptake by modulating hif-1a ubiquitination under hypoxia in breast cancer. Jan 2024. URL: https://doi.org/10.21203/rs.3.rs-3825204/v1, doi:10.21203/rs.3.rs-3825204/v1.

6. (song2025asystematicanalysis pages 8-9): Hao Song, Guojing Wang, Guoqiang Gao, Huayu Xia, Lianying Jiao, and Kaijie Wu. A systematic analysis of expression and function of ras gtpase-activating proteins (rasgaps) in urological cancers: a mini-review. Cancers, 17:1485, Apr 2025. URL: https://doi.org/10.3390/cancers17091485, doi:10.3390/cancers17091485. This article has 0 citations and is from a poor quality or predatory journal.

7. (song2025asystematicanalysis pages 21-21): Hao Song, Guojing Wang, Guoqiang Gao, Huayu Xia, Lianying Jiao, and Kaijie Wu. A systematic analysis of expression and function of ras gtpase-activating proteins (rasgaps) in urological cancers: a mini-review. Cancers, 17:1485, Apr 2025. URL: https://doi.org/10.3390/cancers17091485, doi:10.3390/cancers17091485. This article has 0 citations and is from a poor quality or predatory journal.

8. (fania2024anupdateon pages 7-7): Rossella De Florian Fania, Arianna Bellazzo, and Licio Collavin. An update on the tumor-suppressive functions of the rasgap protein dab2ip with focus on therapeutic implications. Cell Death and Differentiation, 31:844-854, Jun 2024. URL: https://doi.org/10.1038/s41418-024-01332-3, doi:10.1038/s41418-024-01332-3. This article has 6 citations and is from a domain leading peer-reviewed journal.

Citations

1. fania2024anupdateon pages 1-2
2. song2025asystematicanalysis pages 8-9
3. apollonio2023thetumorsuppressor pages 18-19
4. song2025asystematicanalysis pages 21-21
5. fania2024anupdateon pages 2-3
6. fania2024anupdateon pages 7-7
7. https://doi.org/10.1038/s41418-024-01332-3
8. https://doi.org/10.1158/0008-5472.can-22-0370
9. https://doi.org/10.3390/cancers17091485
10. https://doi.org/10.21203/rs.3.rs-3825204/v1
11. https://doi.org/10.3390/cancers15133379
12. https://doi.org/10.3390/cancers17091485;
13. https://doi.org/10.1158/0008-5472.can-22-0370;
14. https://doi.org/10.1038/s41389-024-00523-4;
15. https://doi.org/10.1007/s10142-023-01255-1
16. https://doi.org/10.3390/cancers15133379;
17. https://doi.org/10.1038/s41418-024-01332-3,
18. https://doi.org/10.1158/0008-5472.can-22-0370,
19. https://doi.org/10.3390/cancers15133379,
20. https://doi.org/10.21203/rs.3.rs-3825204/v1,
21. https://doi.org/10.3390/cancers17091485,