PLAT

PLAT encodes tissue-type plasminogen activator (tPA), a serine protease whose proteolytic and signaling activities couple it to growth-factor and survival pathways across multiple tissues (PMID:34520334, PMID:41252074). In the context of cerebral ischemia, tPA degrades IGFBP3 to increase free IGF1 bioavailability, activating the IGF1R tyrosine kinase receptor and the downstream PI3K-AKT-MTOR axis to suppress deleterious autophagy and confer neuroprotection (PMID:34520334). tPA also acts as an upstream signaling molecule that activates Erk1/2, in part through interaction with the kinase Alk, protecting maternally aged oocytes from apoptosis and ferroptosis (PMID:41252074). In bone, PLAT functions downstream of mechanically induced Wnt1/β-Catenin signaling, where it is required for upregulation of the osteogenic markers Runx2 and Sp7 (PMID:38407813). In gefitinib-resistant non-small-cell lung cancer cells, PLAT limits apoptosis and supports survival by preserving mitochondrial function (PMID:32274137). PLAT expression is itself regulated upstream by ADAM9 in tumor angiogenesis and by proximal-promoter CpG methylation, which negatively correlates with its transcription (PMID:29118335, PMID:29962211). The PLAT gene maps to chromosome 8 (PMID:3002960).

1. 1986 Medium

   Establishing the chromosomal location of the human tPA gene was the first step in defining PLAT as a discrete genetic locus.

   Evidence Somatic cell hybrid panel with Southern blotting using a tPA cDNA fragment

   PMID:3002960

   Open questions at the time

   • Does not address gene structure, regulation, or protein function
   • No fine-scale mapping or expression analysis at this stage
2. 2017 Low

   Whether PLAT acts within a defined oncogenic regulatory cascade was unknown; placing it downstream of ADAM9 connected its expression to tumor angiogenesis.

   Evidence Microarray expression and ADAM9 siRNA silencing in lung cancer cells with in vivo tumor growth assays

   PMID:29118335

   Open questions at the time

   • No direct biochemical mechanism linking ADAM9 to PLAT transcription
   • Regulation inferred from expression and knockdown correlation only
3. 2018 Low

   How PLAT transcription is controlled epigenetically was unaddressed; promoter methylation analysis identified specific CpG sites whose hypermethylation suppresses expression.

   Evidence Bisulfite pyrosequencing of proximal-promoter CpG sites with RT-PCR in paired nasal polyp tissue

   PMID:29962211

   Open questions at the time

   • Correlation only, no functional reporter or methyltransferase manipulation
   • Causal direction between methylation and expression not established
4. 2020 Medium

   The role of PLAT in drug-resistant cancer cell survival was unclear; knockdown showed it normally restrains apoptosis by preserving mitochondrial function.

   Evidence Lentiviral PLAT silencing in resistant PC9 cells with mitochondrial membrane potential, flow cytometry, cDNA arrays, and xenografts

   PMID:32274137

   Open questions at the time

   • Molecular link between PLAT and mitochondrial function not resolved
   • Whether protease activity is required is not defined
5. 2021 Medium

   The mechanism of tPA neuroprotection beyond thrombolysis was unknown; tPA was shown to degrade IGFBP3, freeing IGF1 to activate IGF1R/PI3K-AKT-MTOR and suppress autophagy.

   Evidence In vitro hypoxia-reperfusion and in vivo thromboembolic stroke models with pathway inhibitors and human stroke samples

   PMID:34520334

   Open questions at the time

   • Direct enzymatic cleavage of IGFBP3 by tPA not biochemically reconstituted
   • Contribution of plasmin-independent activity not separated
6. 2024 Medium

   Whether PLAT participates in mechanosensitive bone signaling was unknown; it was placed downstream of Wnt1/β-Catenin as a required mediator of osteogenic marker induction.

   Evidence Mechanical stimulation of osteoblasts with Wnt1/Plat siRNA, RNAseq, β-Catenin assays, and OVX/aged mouse models

   PMID:38407813

   Open questions at the time

   • Mechanism by which Plat promotes Runx2/Sp7 expression not defined
   • Direct molecular targets of Plat in osteoblasts unidentified
7. 2025 Medium

   Whether tPA has a survival role in aging gametes was unknown; it was shown to activate Erk1/2 via interaction with Alk to protect aged oocytes from apoptosis and ferroptosis.

   Evidence Single-oocyte transcriptomics, Plat siRNA knockdown, Erk1/2 pathway assays, exogenous tPA rescue, and Alk co-interaction analysis

   PMID:41252074

   Open questions at the time

   • Nature of the tPA-Alk interaction not structurally characterized
   • Whether protease activity is required for Erk1/2 activation unclear
8. 2025 Low

   Extending the cancer survival role, PLAT was linked to migration and invasion of resistant NSCLC cells via a PLAT/FAK/AKT axis.

   Evidence Whole-transcriptome sequencing, pathway western blots, migration/invasion assays, and an in vivo NSG model with ADI treatment

   PMID:39754146

   Open questions at the time

   • PLAT's direct role in FAK activation not reconstituted
   • Pathway placement inferred from expression and inhibition only

• Whether PLAT's diverse tissue functions depend on its protease activity versus non-proteolytic receptor interactions remains unresolved.
• No catalytic-dead mutant comparison across the reported pathways
• Direct substrates and binding partners not biochemically reconstituted
• Unifying mechanism across stroke, oocyte, bone, and cancer contexts undefined