YLPM1

YLPM1 acts as a tumor suppressor in gastrointestinal stromal tumors (GIST), where recurrent inactivating mutations in high-risk and metastatic disease drive cell proliferation, growth, and oxidative phosphorylation upon loss of function (PMID:39489749). Beyond this loss-of-function phenotype, the molecular mechanism of YLPM1 is largely uncharacterized in the available corpus: it has been detected in nuclear Ago2-associated complexes alongside SSBP1 in cardiomyocytes (PMID:31837603), and a YLPM1::PRKD1 gene fusion has been identified in a cribriform polymorphous adenocarcinoma of the salivary gland (PMID:38735907), but neither the consequences of the nuclear interaction nor the function of the fusion protein has been defined.

1. 2019 Low

   To begin placing YLPM1 in a molecular context, it was unknown what protein complexes it participates in; mass spectrometry of nuclear Ago2 complexes established YLPM1 as a physical associate of nuclear Ago2 and SSBP1.

   Evidence LC-MS analysis of nuclear Ago2-associated proteins in cardiomyocytes

   PMID:31837603

   Open questions at the time

   • Single Co-IP/MS experiment with no reciprocal validation of the YLPM1-Ago2 interaction
   • No functional consequence of the YLPM1-Ago2-SSBP1 association established
   • Direct versus indirect nature of the interaction unresolved
2. 2024 Medium

   Whether YLPM1 has a causal role in cancer was unknown; functional study of recurrent inactivating mutations in GIST established YLPM1 as a tumor suppressor whose loss promotes proliferation, growth, and oxidative phosphorylation.

   Evidence Functional loss-of-function study of inactivating YLPM1 mutations in GIST cells with proliferation, growth, and OXPHOS readouts

   PMID:39489749

   Open questions at the time

   • Molecular mechanism linking YLPM1 loss to increased oxidative phosphorylation not defined
   • Single-lab study with limited methodological detail
   • Direct molecular substrates or targets of YLPM1 not identified
3. 2024 Low

   Genomic involvement of YLPM1 in other tumors was unexplored; a case of salivary gland adenocarcinoma revealed a previously unreported YLPM1::PRKD1 fusion, expanding the genomic contexts in which YLPM1 is altered.

   Evidence Molecular pathology / fusion gene identification in a single salivary gland tumor

   PMID:38735907

   Open questions at the time

   • Single case report with no functional characterization of the fusion protein
   • Oncogenic contribution of the fusion not tested
   • Relationship of this rearrangement to YLPM1 loss-of-function in GIST unknown

• The core biochemical activity of YLPM1 and the mechanism by which its inactivation reprograms cell metabolism and proliferation remain undefined.
• No molecular activity or catalytic function defined
• No mechanism connecting YLPM1 loss to oxidative phosphorylation
• Functional significance of nuclear Ago2/SSBP1 association untested