| Claim/Topic | Key finding | Evidence type | Source | Publication date | URL/DOI |
|---|---|---|---|---|---|
| Target identity / core function | Human **RASAL2** corresponds to **RAS protein activator like 2 / nGAP**, a RasGAP-family protein of **1,139 aa**; RasGAPs accelerate conversion of **RAS-GTP to RAS-GDP**, thereby suppressing RAS signaling (pqac-00000002) | Review / domain summary | Stewart, *Journal of Cell Science* | Feb 2020 | https://doi.org/10.1242/jcs.238865 |
| Domains | RASAL2 is described as containing **PH, C2, and C-terminal RasGAP domains**; noncatalytic domains are implicated in membrane targeting/interactions needed to position RasGAPs near membrane-associated RAS (pqac-00000002) | Review | Stewart, *Journal of Cell Science* | Feb 2020 | https://doi.org/10.1242/jcs.238865 |
| Family / current understanding | Review classifies RASAL2 among cytoplasmic RasGAPs and notes that loss of RasGAPs can elevate Ras pathway output; RASAL2 has context-dependent tumor-suppressive or oncogenic roles across cancers (pqac-00000001, pqac-00000002) | Review | Bellazzo, *Cancers*; Stewart, *Journal of Cell Science* | Oct 2020; Feb 2020 | https://doi.org/10.3390/cancers12103066 ; https://doi.org/10.1242/jcs.238865 |
| Localization | Review evidence indicates **PH and C2 domains promote constitutive plasma membrane association**, and **RASAL2 associates with membranes at the leading edge**; however, detailed RASAL2-specific mechanistic localization data remain limited in gathered evidence (pqac-00000009 indirectly notes absence of such data in Olsen excerpt; localization statement from King search context summarized in tool output) (pqac-00000009) | Review / inferred from family biology | King, *Science Signaling* | Feb 2013 | https://doi.org/10.1126/scisignal.2003669 |
| Regulation / PTM | Review notes **RASAL2 can be phosphorylated on Ser237 within the PH domain** and that membrane localization is important for RasGAP activity (pqac-00000001) | Review | Bellazzo, *Cancers* | Oct 2020 | https://doi.org/10.3390/cancers12103066 |
| Regulation / PTM | **AMPK (PRKAA)** phosphorylates **RASAL2 at S351** under glucose starvation; this promotes dissociation from **PPM1B** and enables phosphorylated RASAL2 to bind the **PIK3C3/VPS34-ATG14-BECN1 complex**, increasing PIK3C3 activity and autophagy (pqac-00000003, pqac-00000004) | Primary; cell biology / autophagy assays | Bao, *Autophagy* | Feb 2021 | https://doi.org/10.1080/15548627.2021.1886767 |
| Binding partners / mechanism | Under basal conditions RASAL2 recruits **PPM1B/pp2cβ** to attenuate AMPK phosphorylation; glucose starvation causes **PPM1B dissociation** and converts RASAL2 into an autophagy activator via the VPS34 complex (pqac-00000003, pqac-00000004) | Primary; interaction and functional assays | Bao, *Autophagy* | Feb 2021 | https://doi.org/10.1080/15548627.2021.1886767 |
| Functional nuance | RASAL2’s inhibition of basal autophagy is reported to be **independent of RasGAP catalytic activity**, although the **GAP domain is required** for this inhibitory role (pqac-00000004) | Primary; KO/rescue functional assays | Bao, *Autophagy* | Feb 2021 | https://doi.org/10.1080/15548627.2021.1886767 |
| Regulation / phosphoproteomics | LKB1-dependent phosphoproteomics identified candidate AMPK-related phosphorylation sites on RASAL2: **S56, S89, S736, S864, S899**; phosphoenriched data showed LKB1-dependent increases at **S89, S736, S864** (pqac-00000005, pqac-00000006) | Primary; phosphoproteomics | Kamireddy, phosphoproteomics study | 2020 | URL not available in gathered evidence |
| Upstream kinases | In detachment settings, **SIK1 + SIK3** knockout/knockdown abolished the LKB1-dependent AMPK-motif phospho-signal on RASAL2; **AMPK** contributed partially; **MARKs** were also implicated for some sites (pqac-00000006, pqac-00000007, pqac-00000008) | Primary; phosphoproteomics / IP / kinase KO | Kamireddy, phosphoproteomics study | 2020 | URL not available in gathered evidence |
| Pathways | In cancer literature, RASAL2 loss is linked to enhanced **Ras–ERK/MAPK** signaling; context-dependent reports also connect RASAL2 to **YAP, Wnt/β-catenin, PI3K/AKT, and Rac1** signaling (pqac-00000001, pqac-00000003) | Review + primary mechanistic context | Bellazzo, *Cancers*; Bao, *Autophagy* | Oct 2020; Feb 2021 | https://doi.org/10.3390/cancers12103066 ; https://doi.org/10.1080/15548627.2021.1886767 |
| Disease / breast cancer cohort | In luminal B breast tumors, **16%** showed low **RASAL2**, **24%** low **DAB2IP**, and **22%** low expression of **both**; combined low expression strongly stratified relapse-free survival (**log-rank P = 3.1e-08**) (pqac-00000009, pqac-00000011) | Primary; patient cohort / Kaplan–Meier | Olsen, *Cancer Discovery* | Feb 2017 | https://doi.org/10.1158/2159-8290.CD-16-0520 |
| Disease / metastasis mechanism | In luminal breast cancer models, **RASAL2 and DAB2IP cooperate** to suppress metastasis; reconstitution of both genes reduced metastasis versus single-gene reconstitution or control (**P = 0.043 vs RASAL2 alone; P = 0.002 vs DAB2IP alone; total flux P = 0.004**) (pqac-00000010) | Primary; xenograft / intracardiac metastasis assays | Olsen, *Cancer Discovery* | Feb 2017 | https://doi.org/10.1158/2159-8290.CD-16-0520 |
| Disease / metastatic phenotypes | In McNeu luminal mouse cancer cells, shRNA codepletion of **Rasal2 + Dab2ip** significantly increased metastatic lung lesions after tail-vein injection (**P = 0.0019**) (pqac-00000010) | Primary; mouse metastasis assay | Olsen, *Cancer Discovery* | Feb 2017 | https://doi.org/10.1158/2159-8290.CD-16-0520 |
| Disease / tumor growth | In CAMA1 xenografts, RASAL2 or DAB2IP suppression significantly affected tumor formation/growth (reported P values for individual perturbations include **0.0043, 0.0087** for DAB2IP guides and **0.0016, 0.0022** for RASAL2 shRNAs); combined suppression also reported with **P = 0.008**, though legend notes no statistically significant increase in tumor volume upon combined suppression (pqac-00000009) | Primary; xenograft / CRISPR-shRNA | Olsen, *Cancer Discovery* | Feb 2017 | https://doi.org/10.1158/2159-8290.CD-16-0520 |
| Clinical relevance / expert view | Reviews emphasize that RASAL2 behaves as a **context-dependent RasGAP regulator**: often tumor suppressive when expression is lost and Ras signaling rises, but in some settings capable of promoting EMT/metastatic programs through noncanonical pathway wiring (pqac-00000001, pqac-00000003) | Review / expert synthesis | Bellazzo, *Cancers*; Bao, *Autophagy* | Oct 2020; Feb 2021 | https://doi.org/10.3390/cancers12103066 ; https://doi.org/10.1080/15548627.2021.1886767 |


*Table: This table compiles the key evidence gathered for human RASAL2, covering molecular function, domains, localization, regulation, pathways, and disease relevance. It highlights residue-level PTMs, pathway interactions, and clinically relevant statistics from breast cancer studies.*